Benzazole compounds and methods for making and using the compounds

ABSTRACT

Disclosed are novel benzazole compounds and compositions comprising the compounds. The compounds are useful as kinase inhibitors including interleukin receptor associated kinases (IRAK) inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. §119(e) of theearlier filing date of U.S. Provisional Application No. 62/200,778,filed on Aug. 4, 2015, which is incorporated herein by reference in itsentirety.

FIELD

This disclosure concerns benzazole compounds, and embodiments of amethod for making and using the compounds, such as for inhibitingkinases, including interleukin receptor-associated kinase (IRAK), andfor treating related diseases and conditions.

BACKGROUND

Interleukin-1 receptor-associated kinases (IRAKs) are importantmediators of signaling processes, such as toll-like receptors (TLR) andinterleukin-1 receptor (IL-1R) signaling processes. IRAKs have beenimplicated in modulating signaling networks that control inflammation,apoptosis, and cellular differentiation. Four IRAK genes have beenidentified in the human genome (IRAK1, IRAK2, IRAK3 and IRAK4), andstudies have revealed distinct, non-redundant biological roles. IRAK1and IRAK4 have been shown to exhibit kinase activity.

SUMMARY

Disclosed herein are benzazole compounds, and compositions comprisingsuch compounds, that are useful as, inter alia, immunomodulators, inparticular, the present compounds are kinase inhibitors, such as by wayof example IRAK inhibitors. Certain disclosed embodiments concernbenzazole compounds having a formula I

or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, orprodrug thereof. With respect to formula I, X is 0 or S; Y is 0 or S; Zis N or CR⁹; Het-1 is heterocyclyl; R¹ and R² independently are H,aliphatic, heteroaliphatic, heterocyclyl, aryl, araliphatic, or togetherwith the nitrogen to which they are attached, form a heterocyclic ring;R³, R⁴, R⁵, R⁶ and R⁹ independently are H, aliphatic, halo,heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic,—O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl,amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl; R⁷is H, aliphatic, heteroaliphatic, heterocyclyl, aryl or araliphatic;each R⁸ independently is aliphatic, halo, heteroaliphatic, —O-aliphatic,heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro,cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl,sulfonamide, sulfanyl, sulfinyl or haloalkyl; and m is from 0 to thenumber of possible substituents on Het-1. In some embodiments, X is 0,and in other embodiments, X is S.

Het-1 may be a heteroaryl. Exemplary Het-1 may be selected from furan,thiophene, pyrazole, pyrrole, imidazole, oxazole, thiazole, isoxazole,isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-oxadiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole,1,2,5-thiadiazole, tetrazole, pyrimidine, pyridine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, pyrazine, pyridazine, quinoline,isoquinoline, indole, isoindole, benzofuran, benzothiophene,benzoimidazole, benzopyrazole, benzotriazole, pyrrolo[2,3-b]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,4-b]pyridine or pyrrolo[3,4-c]pyridine. In some embodiments,Het-1 is pyridine, pyrazole or pyrrolo[2,3-b]pyridine, and in particularembodiments,

is selected from

In some embodiments, the compound has a formula selected from

With respect to these formulas, R¹⁰ and R²³ independently are H,aliphatic, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl,araliphatic, —O-heterocyclyl, hydroxyl, cyano, carboxyl, carboxyl ester,acyl, amide, amino, sulfonyl, sulfonamide, or haloalkyl, typically H,aliphatic, aryl or heterocyclyl; and R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,R¹⁸, R¹⁹, R²⁰, R²¹ and R²² independently are H, aliphatic, halogen,heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic,—O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl,amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, or haloalkyl.

In any of the above embodiments, R⁵ may be amino, aryl or heteroaryl. R⁵may be amino having a formula NRR wherein each R independently isaliphatic, or both R groups together with the nitrogen attached theretoform an optionally substituted heterocyclic ring.

R¹ and R² independently may be H, aliphatic, heteroaliphatic, ortogether with the nitrogen attached thereto form a heteroaliphatic ring.In some embodiments, R¹ is H or alkyl, and R² is aliphatic orheteroaliphatic.

In particular embodiments, R³, R⁴, R⁶ and R⁷ are H.

Also disclosed herein are embodiments of a composition comprising abenzazole compound within the scope of the present invention and apharmaceutically acceptable excipient. Disclosed exemplary compositionsmay also comprise a benzazole compound within the scope of the presentinvention and an additional therapeutic agent. Alternatively, thebenzazole compounds, or compositions comprising the benzazole compounds,may be administered as a combination with an additional therapeutic(s).The additional therapeutic agent(s) may comprise an immunooncologyagent. The benzazole compounds, or compositions comprising the benzazolecompounds, and the additional therapeutic agent(s) may be administeredto a subject substantially simultaneously, sequentially in any order, orwithin a time period such that the subject experiences an overlappingbeneficial effect from both the benzazole compound or the compositioncomprising the benzazole compound, and the additional therapeuticagent(s).

Embodiments of a method for administering a benzazole compound orcomposition comprising a benzazole compound(s) are also disclosed. Forexample, disclosed herein are embodiments of a method for inhibiting ormodulating an IRAK protein comprising contacting the IRAK protein withan effective amount of a benzazole compound. In some embodiments, themethod comprises contacting the protein in vitro. In other embodiments,the IRAK protein may be in a subject. Exemplary compounds have an EC₅₀of from greater than 0 to 5 μM, such as from greater than 0 to 1 μM. Incertain embodiments, the method comprises administering to a subject inneed thereof a therapeutically effective amount of a benzazole compoundor composition comprising the benzazole compound. The method may be amethod of treating a disease or condition for which an IRAK modulator orinhibitor is indicated.

The foregoing and other objects, features, and advantages of theinvention will become more apparent from the following detaileddescription.

DETAILED DESCRIPTION I. Definitions

The following explanations of terms and methods are provided to betterdescribe the present disclosure and to guide those of ordinary skill inthe art in the practice of the present disclosure. The singular forms“a,” “an,” and “the” refer to one or more than one, unless the contextclearly dictates otherwise. The term “or” refers to a single element ofstated alternative elements or a combination of two or more elements,unless the context clearly indicates otherwise. As used herein,“comprises” means “includes.” Thus, “comprising A or B,” means“including A, B, or A and B,” without excluding additional elements. Allreferences, including patents and patent applications cited herein, areincorporated by reference.

Unless otherwise indicated, all numbers expressing quantities ofcomponents, molecular weights, percentages, temperatures, times, and soforth, as used in the specification or claims are to be understood asbeing modified by the term “about.” Accordingly, unless otherwiseindicated, implicitly or explicitly, the numerical parameters set forthare approximations that may depend on the desired properties soughtand/or limits of detection under standard test conditions/methods. Whendirectly and explicitly distinguishing embodiments from discussed priorart, the embodiment numbers are not approximates unless the word “about”is recited.

Unless explained otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this disclosure belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, suitable methods andmaterials are described below. The materials, methods, and examples areillustrative only and not intended to be limiting.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to include hydrogen so thateach carbon conforms to a valence of four. For example, in the structureon the left-hand side of the schematic below there are nine hydrogenatoms implied. The nine hydrogen atoms are depicted in the right-handstructure.

Sometimes a particular atom in a structure is described in textualformula as having a hydrogen or hydrogen atoms, for example —CH₂CH₂—. Itwill be understood by a person of ordinary skill in the art that theaforementioned descriptive techniques are common in the chemical arts toprovide brevity and simplicity to description of organic structures.

A person of ordinary skill in the art will appreciate that thedefinitions may be combined to further describe a particular compound.For example, hydroxyaliphatic refers to an aliphatic group substitutedwith an hydroxy (—OH) group, and haloalkylaryl refers to an aryl groupsubstituted with an alkyl group, where the alkyl group too issubstituted with a halogen, and where the point of attachment to theparent structure is via the aryl moiety since aryl is the base name ofthe substituent.

As used herein, the term “substituted” refers to all subsequentmodifiers in a term, for example in the term “substituted arylC₁₋₈alkyl,” substitution may occur on the “C₁₋₈ alkyl” portion, the “aryl”portion or both portions of the arylC₁₋₈ alkyl group. Also by way ofexample, alkyl includes substituted cycloalkyl groups.

“Substituted,” when used to modify a specified group or moiety, meansthat at least one, and perhaps two or more, hydrogen atoms of thespecified group or moiety is independently replaced with the same ordifferent substituent groups as defined below. In a particularembodiment, a group, moiety or substituent may be substituted orunsubstituted, unless expressly defined as either “unsubstituted” or“substituted.” Accordingly, any of the groups specified herein may beunsubstituted or substituted. In particular embodiments, the substituentmay or may not be expressly defined as substituted, but is stillcontemplated to be optionally substituted. For example, an “alkyl”substituent may be unsubstituted or substituted, but an “unsubstitutedalkyl” may not be substituted.

“Substituents” or “substituent groups” for substituting for one or morehydrogen atoms on saturated carbon atoms in the specified group ormoiety may be any atom, or group of atoms, that a person of ordinaryskill in the art would recognize as a suitable substituent orsubstituent group. Substituents” or “substituent groups” are, unlessotherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰, —N(R⁸⁰)₂, haloalkyl,perhaloalkyl, —CN, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰,—OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(O⁻)₂M²⁺, —P(O)(OR⁷⁰)O⁻M⁺,—P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰,—C(S)OR⁷⁰, —C(O)N(R⁸⁰)₂, —C(NR⁷⁰)(R⁸⁰)₂, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺,—NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰ is C₁₋₆ alkyl; each R⁷⁰ is independentlyfor each occurrence hydrogen or R⁶⁰; each R⁸⁰ is independently for eachoccurrence R⁷⁰ or alternatively, two R⁸⁰ groups, taken together with thenitrogen atom to which they are bonded, form a 3- to 7-memberedheteroalicyclyl which optionally includes from 1 to 4 of the same ordifferent additional heteroatoms selected from O, N and S, of which Noptionally has H or C₁-C₃alkyl substitution; and each M⁺ is a counterion with a net single positive charge. Each M⁺ is independently for eachoccurrence, for example, an alkali metal ion, such as K⁺, Na⁺, Li⁺; anammonium ion, such as +N(R⁶⁰)₄; or an alkaline metal earth ion, such as[Ca²]_(0.5), [Mg²]_(0.5), or [Ba²]_(0.5) (a subscript “0.5” means, forexample, that one of the counter ions for such divalent alkali earthions can be an ionized form of a compound of the invention and the othera typical counter ion such as chloride, or two ionized compounds canserve as counter ions for such divalent alkali earth ions, or a doublyionized compound can serve as the counter ion for such divalent alkaliearth ions). As specific examples, —N(R⁸⁰)₂ includes —NH₂, —NH-alkyl,—NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl,4N-methyl-piperazin-1-yl, N-morpholinyl and the like. Any two hydrogenatoms on a single carbon can be replaced with ═O, ═N_(R) ⁷⁰, ═N—OR⁷⁰,═N₂ or ═S.

Substituent groups for replacing hydrogen atoms on unsaturated carbonatoms in groups containing unsaturated carbons are, unless otherwisespecified, —R⁶⁰, halo, —O⁻M³⁰, —OR⁷⁰, —SR⁷⁰, —N(R⁸⁰)₂,

perhaloalkyl, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —PO₃ ⁻²M²⁺,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)N(R⁸⁰)₂, —OC(O)R⁷⁰,—OC(S)R⁷⁰, —O CO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰,—NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂,—NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ areas previously defined, provided that in case of substituted alkene oralkyne, the substituents are not —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, or —S⁻M⁺.

Substituent groups for replacing hydrogen atoms on nitrogen atoms ingroups containing such nitrogen atoms are, unless otherwise specified,—R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —N(R⁸⁰)₂,

perhaloalkyl, —CN, —NO, —NO₂, —S(O)₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OS(O)₂R⁷⁰,—OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃ ²⁻(M⁺)₂, —PO₃ ²⁻M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰,—NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined.

In one embodiment, a group that is substituted has 1 substituent, 2substituents, 3 substituents, or 4 substituents.

Additionally, in embodiments where a group or moiety is substituted witha substituted substituent, the nesting of such substituted substituentsis limited to three, thereby preventing the formation of polymers. Thus,in a group or moiety comprising a first group that is a substituent on asecond group that is itself a substituent on a third group, which isattached to the parent structure, the first (outermost) group can onlybe substituted with unsubstituted substituents. For example, in a groupcomprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substitutedwith substituents that are not themselves substituted.

“Acyl” refers to the group —C(O)R, where R is H, aliphatic,heteroaliphatic, heterocyclic or aryl. Exemplary acyl moieties include,but are not limited to, —C(O)H, —C(O)alkyl, —C(O)C₁-C₆alkyl,—C(O)C₁-C₆haloalkyl-C(O)cycloalkyl, —C(O)alkenyl, —C(O)cycloalkenyl,—C(O)aryl, —C(O)heteroaryl, or —C(O)heterocyclyl. Specific examplesinclude, —C(O)H, —C(O)Me, —C(O)Et, or —C(O)cyclopropyl.

“Aliphatic” refers to a substantially hydrocarbon-based group or moiety,including alkyl, alkenyl, alkynyl groups, cyclic versions thereof, suchas cycloalkyl, cycloalkenyl or cycloalkynyl, and further includingstraight- and branched-chain arrangements, and all stereo and positionalisomers as well. Unless expressly stated otherwise, an aliphatic groupcontains from one to twenty-five carbon atoms; for example, from one tofifteen, from one to ten, from one to six, or from one to four carbonatoms. Unless expressly stated otherwise, a cyclic aliphatic groupcontains from three to twenty-five carbon atoms; for example, from threeto fifteen, from three to ten, or from three to six, carbon atoms.“Lower aliphatic” refers to an aliphatic group, including alkyl, alkenyland alkynyl containing from one to ten carbon atoms, such as from one tosix carbon atoms, or from three to ten carbon atoms, such as from threeto six carbon atoms, for a cyclic lower aliphatic group. An aliphaticgroup may be substituted or unsubstituted, unless expressly referred toas an “unsubstituted aliphatic” or a “substituted aliphatic.” Analiphatic group can be substituted with one or more substituents (up totwo substituents for each methylene carbon in an aliphatic chain, or upto one substituent for each carbon of a —C═C— double bond in analiphatic chain, or up to one substituent for a carbon of a terminalmethine group).

“Alkoxy” refers to the group OR, where R is a substituted orunsubstituted alkyl or cycloalkyl group. In certain examples R is a C₁₋₆alkyl or C₃₋₆ cycloalkyl group. Methoxy (—OCH₃) and ethoxy (—OCH₂CH₃)are exemplary alkoxy groups. In a substituted alkoxy, R is substitutedalkyl or substituted cycloalkyl, examples of which useful in thepresently disclosed compounds include haloalkoxy groups, such as —OCF₂H,and —OCF₃.

“Alkoxyalkyl” refers to the group alkyl-OR, where R is a substituted orunsubstituted alkyl or cycloalkyl group. —CH₂CH₂—O—CH₂CH₃ is anexemplary alkoxyalkyl group.

“Alkyl” refers to a saturated aliphatic hydrocarbyl group having from 1to 25 carbon atoms, typically 1 to 10 carbon atoms such as 1 to 6 carbonatoms and may be designated as C₁-C₆alkyl. An alkyl moiety may besubstituted or unsubstituted. This term includes, by way of example,linear and branched hydrocarbyl groups such as methyl (CH₃), ethyl(—CH₂CH₃), n-propyl (—CH₂CH₂CH₃), isopropyl (—CH(CH₃)₂), n-butyl(—CH₂CH₂CH₂CH₃), isobutyl (—CH₂CH₂(CH₃)₂), sec-butyl (—CH(CH₃)(CH₂CH₃),t-butyl (—C(CH₃)₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), and neopentyl(—CH₂C(CH₃)₃).

“Amino” refers to the group —NH₂, —NHR, or —NRR, where each Rindependently is selected from H, aliphatic, heteroaliphatic, aryl orheterocyclic, or two R groups together with the nitrogen attachedthereto form a heterocyclic ring. Examples of such heterocyclic ringsinclude those wherein two R groups together with the nitrogen to whichthey are attached form a —(CH₂)₂₋₅— ring optionally interrupted by oneor two heteratom groups, such as —O— or —N(R^(g)) such as in the groups

wherein R^(g) is R⁷⁰, —C(O)R⁷⁰, —C(O)OR⁶⁰ or —C(O)N(R⁸⁰)₂.

“Amide” refers to the group —N(H)acyl, or —C(O)amino.

“Aryl” or “aromatic” refers to an aromatic group of, unless specifiedotherwise, from 5 to 15 ring atoms having a single ring (e.g., phenyl)or multiple fused rings in which at least one ring is aromatic (e.g.,naphthyl). Aryl groups may be, for example, monocyclic, bicyclic,tricyclic or tetracyclic. For groups having multiple rings, at least oneof which is aromatic and one is not, such groups are neverthelessreferred to as “aryl” provided that the point of attachment to theremainder of the compound is through an atom of an aromatic portion ofthe aryl group. Unless otherwise stated, an aryl group may besubstituted or unsubstituted.

“Araliphatic” refers to an aryl group attached to the parent via analiphatic moiety. Araliphatic includes aralkyl or arylalkyl groups suchas benzyl and phenylethyl.

“Azole” refers to a five-membered nitrogen heterocyclic ring thatcontains at least one other non-carbon atom typically selected fromnitrogen, sulfur or oxygen. A “benzazole” is a fused ring comprising anazole ring and a phenyl ring. Exemplary benzazoles include, but are notlimited to, benzthiazole, benzoxazole and benzimidazole.

“Carboxyl,” or “carboxy” refer to —CO₂H.

“Carboxylate” refers to —C(O)O⁻ or salts thereof.

“Carboxyl ester” or “carboxy ester” refers to the group C(O)OR, where Ris aliphatic, aryl, heteroaliphatic, and heterocyclic, includingheteroaryl.

“Cyano” refers to the group —CN.

“Cycloaliphatic” refers to a cyclic aliphatic group having a single ring(e.g., cyclohexyl), or multiple rings, such as in a fused, bridged orspirocyclic system, at least one of which is aliphatic, provided thatthe point of attachment is through an atom of an aliphatic region of thecycloaliphatic group. Cycloaliphatic includes saturated and unsaturatedsystems, including cycloalkyl, cycloalkenyl and cycloalkynyl. Exemplarycycloaliphatic groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, orcyclohexenyl.

“Halo,” “halide” or “halogen” refers to fluoro, chloro, bromo or iodo.

“Heteroaliphatic” refers to an aliphatic compound or group having atleast one heteroatom, i.e., one or more carbon atoms has been replacedwith an atom having at least one lone pair of electrons, typicallynitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroaliphaticcompounds or groups may be substituted or unsubstituted, branched orunbranched, acyclic or cyclic, such as a heteroalicyclyl group, chiralor achiral, and may include heterocycle, heterocyclyl,heterocycloaliphatic, or heterocyclic groups. One example of aheteroaliphatic group is CH₃OCH₂CH₂—.

“Heteroaryl” refers to an aryl group where one or more carbon atoms,such as methine (—CH═) or vinylene (—CH═CH—) groups, have been replacedby trivalent or divalent heteroatoms, respectively, in such a way as tomaintain aromaticity, such as determined by the continuous, delocalizedπ-electron system characteristic of the aromatic group, and the numberof out of plane π-electrons corresponding to the Hückel rule (4n+2).

“Heterocycloalkyl” and “heterocyclylalkyl” refer to a heterocyclylmoiety attached to the parent structure via an alkyl moiety, forexample, (tetrahydropyran-4-yl)methyl, (pyridine-4-yl)methyl,morpholinoethyl or piperazin-1-ylethyl.

“Heterocyclyl,” “heterocyclo” “heterocyclic” and “heterocycle” refer toaromatic and non-aromatic ring systems, and more specifically refer to astable three- to fifteen-membered ring moiety comprising carbon atomsand at least one heteroatom, such as from one to five heteroatoms.Typical heteroatoms include, but are not limited to, N, O, S, P, Si orB. The heterocyclyl moiety may be a monocyclic moiety, or may comprisemultiple rings, such as in a bicyclic or tricyclic ring system, providedthat at least one of the rings contains a heteroatom. Such a multiplering moiety can include fused or bridged ring systems as well asspirocyclic systems; and the nitrogen, phosphorus, carbon, silicon orsulfur atoms in the heterocyclyl moiety can be optionally oxidized tovarious oxidation states. For convenience, nitrogens, particularly butnot exclusively, those defined as annular (in the ring) aromaticnitrogens, are meant to include their corresponding N-oxide form,although not explicitly defined as such in a particular example. Thus,for a compound having, for example, a pyridyl ring, the correspondingpyridyl-N-oxide is included as another compound of the invention, unlessexpressly excluded by context. In addition, annular nitrogen atoms canbe optionally quaternized. Heterocyclyl includes heteroaryl moieties andheteroalicyclyl or heterocycloaliphatic moieties, which are heterocyclylrings that are partially or fully saturated. Thus a term such as“heterocyclylalkyl” includes heteroalicyclylalkyls and heteroarylalkyls.Examples of heterocyclyl groups include, but are not limited to,azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolopyridinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane,diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxaphospholanyl, and oxadiazolyl.

“Hydroxyl” refers to the group —OH.

“Nitro” refers to the group —NO₂.

“Patient” or “Subject” refers to mammals and other animals, particularlyhumans. Thus, disclosed methods are applicable to both human therapy andveterinary applications.

“Pharmaceutically acceptable excipient” refers to a substance, otherthan an active ingredient, that is included in a formulation of anactive ingredient. As used herein, an excipient may be incorporatedwithin particles of a pharmaceutical composition, or it may bephysically mixed with particles of a pharmaceutical composition. Anexcipient can be used, for example, to dilute an active agent and/or tomodify properties of a pharmaceutical composition. Excipients caninclude, but are not limited to, antiadherents, binders, coatings,enteric coatings, disintegrants, flavorings, sweeteners, colorants,lubricants, glidants, sorbents, preservatives, adjuvants, carriers orvehicles. Excipients may be starches and modified starches, celluloseand cellulose derivatives, saccharides and their derivatives such asdisaccharides, polysaccharides and sugar alcohols, protein, syntheticpolymers, crosslinked polymers, antioxidants, amino acids orpreservatives. Exemplary excipients include, but are not limited to,magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose,starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose,xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP),polyethyleneglycol (PEG), tocopheryl polyethylene glycol 1000 succinate(also known as vitamin E TPGS, or TPGS), carboxy methyl cellulose,dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitaminC, retinyl palmitate, selenium, cysteine, methionine, citric acid,sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc,magnesium carbonate, sodium starch glycolate, tartrazine, aspartame,benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulphiteor lanolin.

An “adjuvant” is an excipient that modifies the effect of other agents,typically the active ingredient. Adjuvants are often pharmacologicaland/or immunological agents. An adjuvant may modify the effect of anactive ingredient by increasing an immune response. An adjuvant may alsoact as a stabilizing agent for a formulation. Exemplary adjuvantsinclude, but are not limited to, aluminum hydroxide, alum, aluminumphosphate, killed bacteria, squalene, detergents, cytokines, paraffinoil, and combination adjuvants, such as Freund's complete adjuvant orFreund's incomplete adjuvant.

“Pharmaceutically acceptable carrier” refers to an excipient that is acarrier or vehicle, such as a suspension aid, solubilizing aid, oraerosolization aid. See, for example, Remington: The Science andPractice of Pharmacy, The University of the Sciences in Philadelphia,Editor, Lippincott, Williams, & Wilkins, Philadelphia, Pa., 21^(st)Edition (2005), incorporated herein by reference, which describescompositions and formulations suitable for pharmaceutical delivery ofone or more therapeutic compositions and additional pharmaceuticalagents.

In general, the nature of the carrier will depend on the particular modeof administration being employed. For instance, parenteral formulationsusually comprise injectable fluids that include pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. In some examples, the pharmaceutically acceptable carrier maybe sterile to be suitable for administration to a subject (for example,by parenteral, intramuscular, or subcutaneous injection). In addition tobiologically-neutral carriers, pharmaceutical compositions to beadministered can contain minor amounts of non-toxic auxiliarysubstances, such as wetting or emulsifying agents, preservatives, and pHbuffering agents and the like, for example sodium acetate or sorbitanmonolaurate.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound that are derived from a variety of organic andinorganic counter ions as will be known to a person of ordinary skill inthe art and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate, and the like. “Pharmaceutically acceptable acidaddition salts” are a subset of “pharmaceutically acceptable salts” thatretain the biological effectiveness of the free bases while formed byacid partners. In particular, the disclosed compounds form salts with avariety of pharmaceutically acceptable acids, including, withoutlimitation, inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like, as well asorganic acids such as formic acid, acetic acid, trifluoroacetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid,isethionic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, xinafoic acid and the like.“Pharmaceutically acceptable base addition salts” are a subset of“pharmaceutically acceptable salts” that are derived from inorganicbases such as sodium, potassium, lithium, ammonium, calcium, magnesium,iron, zinc, copper, manganese, aluminum salts and the like. Exemplarysalts are the ammonium, potassium, sodium, calcium, and magnesium salts.Salts derived from pharmaceutically acceptable organic bases include,but are not limited to, salts of primary, secondary, and tertiaryamines, substituted amines, including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplaryorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline, and caffeine. (See, forexample, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977; 66:1-19 which is incorporated herein by reference.) In particulardisclosed embodiments, the benzazole compound may be a formate or sodiumsalt.

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound sufficient to treat a specifieddisorder or disease, or to ameliorate or eradicate one or more of itssymptoms and/or to prevent the occurrence of the disease or disorder.The therapeutically effective amount can be determined by a person ofordinary skill in the art.

“Prodrug” refers to a compound that is transformed in vivo to yield abiologically active compound, particularly the parent compound, forexample, by hydrolysis in the gut or enzymatic conversion. Commonexamples of prodrug moieties include, but are not limited to, ester andamide forms of a compound having an active form bearing a carboxylicacid moiety. Examples of pharmaceutically acceptable esters of thecompounds of this invention include, but are not limited to, esters ofphosphate groups and carboxylic acids, such as aliphatic esters,particularly alkyl esters (for example C₁₋₆ alkyl esters). Other prodrugmoieties include phosphate esters, such as —CH₂—O—P(O)(OR′)₂ or a saltthereof, wherein R′ is H or lower alkyl, such as C₁₋₆alkyl. Acceptableesters also include cycloalkyl esters and arylalkyl esters such as, butnot limited to, benzyl. Examples of pharmaceutically acceptable amidesof the compounds of this invention include, but are not limited to,primary amides, and secondary and tertiary alkyl amides (for examplewith between about one and about six carbons). Amides and esters ofdisclosed exemplary embodiments of compounds according to the presentinvention can be prepared according to conventional methods. A thoroughdiscussion of prodrugs is provided in T. Higuchi and V. Stella,“Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. SymposiumSeries, and in Bioreversible Carriers in Drug Design, ed. Edward B.Roche, American Pharmaceutical Association and Pergamon Press, 1987,both of which are incorporated herein by reference for all purposes.

“Solvate” refers to a complex formed by a combination of solventmolecules with molecules or ions of the solute. The solvent can be anorganic compound, an inorganic compound, or a mixture of both. Someexamples of solvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.The compounds described herein can exist in un-solvated as well assolvated forms when combined with solvents, pharmaceutically acceptableor not, such as water, ethanol, and the like. Solvated forms of thepresently disclosed compounds are within the scope of the embodimentsdisclosed herein. A “hydrate” is a complex formed by a combination ofwater molecules with molecules or ions of the solute.

“Sulfonamide” refers to the group or moiety —SO₂amino, or—N(R^(c))sulfonyl, where R^(c) is H, aliphatic, aryl, heteroaliphatic,cyclic, and heterocyclic, including heteroaryl.

“Sulfanyl” refers to the group or —SH, —S-aliphatic, —S-aryl,—S-heteroaliphatic, —S-cyclic, —S-heterocyclyl, including —S-heteroaryl.

“Sulfinyl” refers to the group or moiety —S(O)H, —S(O)aliphatic,—S(O)aryl, —S(O)heteroaliphatic, —S(O)cyclic, —S(O)heterocyclyl,including —S(O)heteroaryl.

“Sulfonyl” refers to the group: —SO₂H, —SO₂aliphatic, —SO₂aryl,—SO₂heteroaliphatic, —SO₂cyclic, —SO₂heterocyclyl, including—SO₂heteroaryl.

“Treating” or “treatment” as used herein concerns treatment of a diseaseor condition of interest in a patient or subject, including human oranimal subjects, particularly a human having the disease or condition ofinterest, and includes by way of example, and without limitation:

(i) preventing the disease or condition from occurring in a patient orsubject, in particular, when such patient or subject is predisposed tothe condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease or condition, for example, arresting orslowing its development;

(iii) relieving the disease or condition, for example, causingregression of the disease or condition or a symptom thereof; or

(iv) stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” can be usedinterchangeably or can be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been determined) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, where a more or lessspecific set of symptoms have been identified by clinicians.

The above definitions and the following general formulas are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluoro groups). Such impermissible substitutionpatterns are easily recognized by a person having ordinary skill in theart.

Any of the groups referred to herein may be optionally substituted by atleast one, possibly two or more, substituents as defined herein. Thatis, a substituted group has at least one, possible two or more,substitutable hydrogens replaced by a substituent or substituents asdefined herein, unless the context indicates otherwise or a particularstructural formula precludes substitution.

A person of ordinary skill in the art will appreciate that compounds mayexhibit the phenomena of tautomerism, conformational isomerism,geometric isomerism, and/or optical isomerism. For example, certaindisclosed compounds can include one or more chiral centers and/or doublebonds and as a consequence can exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers,diasteromers, and mixtures thereof, such as racemic mixtures. As anotherexample, certain disclosed compounds can exist in several tautomericforms, including the enol form, the keto form, and mixtures thereof. Asthe various compound names, formulae and compound drawings within thespecification and claims may represent only one of the possibletautomeric, conformational isomeric, optical isomeric, or geometricisomeric forms, it will be understood that the disclosed compoundsencompass any tautomeric, conformational isomeric, optical isomeric,and/or geometric isomeric forms of the compounds described herein, aswell as mixtures of these various different isomeric forms, unless thecontext indicates that a single such isomer is intended. In cases oflimited rotation, e.g. around the amide bond or between two directlyattached rings such as the thiazole and pyridyl rings, atropisomers arealso possible and are also specifically included in the compounds of theinvention.

II. Benzazole Compounds and Compositions Thereof

A. Benzazole Compounds

Disclosed herein are benzazole compounds, methods of making thecompounds, and methods of using the compounds. In one embodiment, thedisclosed compounds are tyrosine kinase inhibitors. In a particularembodiment, the compounds are useful in blocking one or more cytokinesignaling pathways, such as the IL-17 signaling pathway. For certainembodiments, the benzazole compounds are useful for treating conditionsin which inhibition of an interleukin-1 receptor-associated kinase(IRAK) pathway is therapeutically useful. In some embodiments, thecompounds directly inhibit an IRAK protein, such as IRAK1, IRAK2, IRAK3or IRAK4.

Exemplary benzazole compounds within the scope of the present disclosurehave a general formula I

or a pharmaceutically acceptable salt, solvent, hydrate, N-oxide,prodrug, or combination thereof. With respect to formula I, Het-1 is aheterocyclyl, typically a heteroaryl; X is O or S; Y is O or N; and Z isS or CR⁹. R¹ and R² independently are H; aliphatic, including alkyl,alkenyl, alkynyl, cycloalkyl, and cycloalkenyl; heteroaliphatic;heterocyclyl, including heteroaryl and heterocycloaliphatic; aryl oraraliphatic; or together with the nitrogen to which they are attached,form an optionally substituted heterocyclic ring. R³, R⁴, R⁵, R⁶ and R⁹independently are H; aliphatic, including alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl and cycloalkynyl; halogen; heteroaliphatic;—O-aliphatic, such as alkoxy; heterocyclyl, including heteroaryl andheterocycloaliphatic; aryl; araliphatic; —O-heterocyclyl; hydroxyl;nitro; cyano; carboxyl; carboxyl ester; acyl; amide; amino; sulfonyl;sulfonamide; sulfanyl; sulfinyl; or haloalkyl; R⁷ is H; aliphatic,including alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl;heteroaliphatic; heterocyclyl, including heteroaryl andheterocycloaliphatic; aryl or araliphatic; or any two adjacent groups,such as R⁴ and R⁵, R⁵ and R⁷, R⁷ and R⁶ and/or R⁶ and R⁹, independently,together may form an aryl, heteroaryl, cycloaliphatic or heterocyclylring. Each R⁸ independently is aliphatic, including alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; halogen;heteroaliphatic; —O-aliphatic, such as alkoxy; heterocyclyl, includingheteroaryl and heterocycloaliphatic; aryl; araliphatic; —O-heterocyclyl;hydroxyl; nitro; cyano; carboxyl; carboxyl ester; acyl; amide; amino;sulfonyl; sulfonamide; sulfanyl; sulfinyl; or haloalkyl; and m is from 0to the number of possible substituents on Het-1, such as from 0 to 1, 2,3, 4, 5, or at least 6. Het-1 can be unsubstituted (when m is 0) orsubstituted. If Het-1 is unsubstituted a person of ordinary skill in theart will appreciate that there are sufficient implicit hydrogens on allcarbons and heteroatoms to satisfy valance requirements. In particularembodiments of the disclosed benzazole compounds, each R⁸ independentlyis selected from halo, C₁₋₆ haloalkyl such as —CF₃, —CF₂H and —CH₂CF₃,C₁₋₆ alkyl, —OC₁₋₆ alkyl, amino or —CH₂OP(O)(OR²⁴)₂ wherein each R²⁴ isindependently H, C₁₋₆ alkyl or a counterion forming for example apharmaceutically acceptable base addition salt with the phosphatemoiety. In certain embodiments, at least one R⁸ is amino, such as —NH₂;alkyl, such as C₁-C₆alkyl, such as methyl; or haloalkyl such as —CF₃,—CF₂H or —CH₂CF₃. In particular embodiments, m is 1 and R⁸ is —NH₂ ormethyl.

For certain embodiments, Het-1 may be an optionally substituted 5- or6-membered monocyclic heteroaryl or a fused heteroaryl comprising a 5-and/or 6-membered heteroaryl. In some examples, Het-1 is furan;thiophene; pyrazole; pyrrole; imidazole; oxazole; thiazole; isoxazole;isothiazole; triazole, such as 1,2,3-triazole, 1,2,4-triazole, or1,3,4-triazole; oxadiazole, such as 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4-oxadiazole or 1,2,5-oxadiazole; thiadiazole, such as1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole or1,2,5-thiadiazole; tetrazole; pyrimidine; pyridine; triazine, such as1,2,3-triazine, 1,2,4-triazine or 1,3,5-triazine; pyrazine; pyridazine;quinoline; isoquinoline; indole; isoindole; benzofuran; benzothiophene;benzoimidazole; benzopyrazole; benzotriazole; or pyrrolopyridine, suchas pyrrolo[2,3-b]pyridine, pyrrolo[3,2-b]pyridine,pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,4-b]pyridineor pyrrolo[3,4-c]pyridine. In particular examples, Het-1 is pyrazole,pyridine or pyrrolo[2,3-b]pyridine, such as pyrazol-1-yl, pyrazol-3-yl,pyrazol-4-yl, pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,pyrrolo[2,3-b]pyridin-5-yl, pyrrolo[2,3-b]pyridin-2-yl,pyrrolo[2,3-b]pyridin-3-yl, pyrrolo[2,3-b]pyridin-4-yl orpyrrolo[2,3-b]pyridin-6-yl.

Examples of such Het-1 groups are represented by

where R¹⁰ and R²³ are selected from H, aliphatic, heteroaliphatic,—O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl,hydroxyl, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl,sulfonamide, or haloalkyl.

In particular embodiments,

is selected from

In certain embodiments, R⁵ is amino, aryl or heterocyclyl. In someembodiments, R⁵ is amino having a formula —NRR wherein each Rindependently is H or aliphatic, or both R groups together with thenitrogen attached thereto form a heterocyclic ring. In certainembodiment, R⁵ is a cyclic amino selected from

In other embodiments, R⁵ is selected from

In some embodiments, R¹ and R² together with the nitrogen attachedthereto form a heterocyclic ring, typically a heteroaliphatic ring. Incertain embodiments, the heteroaliphatic ring is morpholine, piperidineor piperazine. In other embodiments, R¹ and R² independently are H,aliphatic or heteroaliphatic. In certain examples, R¹ is H or alkyl,such as methyl, ethyl, propyl or isopropyl. In other embodiments, R² isaliphatic or heteroaliphatic. In certain embodiments, R² is aliphaticsubstituted with a heterocycloaliphatic. In particular embodiments, the—N(R¹)(R²) moiety is selected from

where R^(a) is aliphatic, haloalkyl or acyl; n is 1 or 2; and p is 0, 1or 2. R^(a) may be alkyl, haloalkyl or acyl, such as CH₃, CF₃, CF₂H, orR^(b)C(O)—. In some embodiments, R^(b) is aliphatic or haloalkyl, suchas alkyl or haloalkyl, and in certain embodiments, R^(b) is CH₃, CF₃ orCF₂H.

Also with respect to formula I, Het-1 may be: 1A) a 5-memberedheteroaryl; 1B) a 6-membered heteroaryl; 1C) a fused heteroaryl; 1D)selected from pyridine, pyrazole, or pyrrolopyridine; 1E) pyridine; 1F)pyrazole; 1G) pyrrolopyridine; 1H) pyridin-4-yl; 1I) pyridin-4-ylsubstituted at least at the 2-position; 1J) pyridin-4-yl substituted atleast at the 2-position with an alkyl moiety; 1K) 2-methylpyridin-4-yl;1L) pyridin-3-yl; 1M) pyridin-3-yl substituted at least at the6-position; 1N) pyridin-3-yl substituted at least at the 6-position withan amino moiety; 10) 6-aminopyridin-3-yl; 1P) pyrazol-4-yl; 1Q)pyrazol-3-yl; or 1R) pyrrolo[2,3-b]pyridin-5-yl.

With respect to Het-1 embodiments 1A to 1R, R⁵ may be, in combinationwith 1A to 1R: 2A) 5-membered heterocyclyl; 2B) 6-membered heterocyclyl;2C) selected from piperidine, morpholine or pyrrolidine; 2D) piperidine;2E) morpholine; 2F) pyrrolidine; 2G) piperidin-1-yl; 2H)4-fluoropiperidin-1-yl; 21) 4,4-difluoropiperidin-1-yl; 2J)3-fluoropiperidin-1-yl; 2K) 3,3-difluoropiperidin-1-yl; 2L)pyrrolidin-1-yl; or 2M) morpholino.

A person of ordinary skill in the art will understand that any of 2A to2M may be combined with any of 1A to 1R, to form any and allcombinations between such substituents.

With respect to the Het-1 embodiments 1A to 1R and the R⁵ embodiments 2Ato 2M, the —N(R¹)(R²) moiety may be, in any combination with 1A to 1Rand 2A to 2M: 3A) heterocyclyl; 3B) selected such that R¹ and R²independently are H, aliphatic or heteroaliphatic; 3C) morpholine; 3D)piperidine; 3E) piperazine; 3F) 4-methyl-1-piperazinyl; 3G) morpholino;3H) piperidin-1-yl; 31) selected such that R¹ is alkyl and R² isheteroaliphatic; 3J) selected such that R¹ is H or alkyl and R² is alkylsubstituted with a heterocycloaliphatic; 3K)N-(2-methoxyethyl)-N-methylamino; 3L)N-methyl-N-(2-morpholinoethyl)amino; or 3M) (2-morpholinoethyl)amino.

A person of ordinary skill in the art will understand that any of 3A to3M may be combined with any of 1A to 1R and 2A to 2M, to form any andall combinations between such substituents.

With respect to the Het-1 embodiments 1A to 1R, the R⁵ embodiments 2A to2M, and the —N(R¹)(R²) moiety embodiments 3A to 3M, X may be, in anycombination with 1A to 1R, 2A to 2M and 3A to 3M: 4A) oxygen; or 4B)sulfur.

A person of ordinary skill in the art will understand that either of 4Aor 4B may be combined with any of 1A to 1R, 2A to 2M and 3A to 3M, toform any and all combinations between such substituents.

With respect to the Het-1 embodiments 1A to 1R, the R⁵ embodiments 2A to2M, the —N(R¹)(R²) moiety embodiments 3A to 3M and the X embodiments 4Ato 4B, Y may be, in any combination with 1A to 1R, 2A to 2M, 3A to 3Mand 4A to 4B: 5A) oxygen; or 5B) sulfur.

A person of ordinary skill in the art will understand that either of 5Aor 5B may be combined with any of 1A to 1R, 2A to 2M, 3A to 3M and 4A to4B, to form any and all combinations between such substituents.

With respect to the Het-1 embodiments 1A to 1R, the R⁵ embodiments 2A to2M, the —N(R¹)(R²) moiety embodiments 3A to 3M, the X embodiments 4A to4B, and the Y embodiments 5A to 5B, Z may be, in any combination with 1Ato 1R, 2A to 2M, 3A to 3M, 4A to 4B and 5A to 5B: 6A) nitrogen; or 6B)CH.

A person of ordinary skill in the art will understand that either of 6Aor 6B may be combined with any of 1A to 1R, 2A to 2M, 3A to 3M, 4A to 4Band 5A to 5B to form any and all combinations between such substituents.

In some embodiments of formula I, Y is O and Z is CR⁹, leading tocompounds having a formula II

In other embodiments of formula I, Y is S and Z is N, leading tocompounds having a formula III

With respect to formulas II and III, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,m, Het-1 and X are as previously defined for formula I.

In some examples of formula I, Het-1 is pyrazole, pyridine orpyrrolopyridine, leading to compounds having a formula selected from

With respect to formulas IV, V and VI, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, X, Y and Z are as previously defined for formula I, and R¹⁰ and R²³are selected from H, aliphatic, heteroaliphatic, —O-aliphatic,heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, cyano,carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, orhaloalkyl. Certain substituents, such as R⁸, in these formulae, are notshown directly bonded to an atom in the ring. This indicates thatsubstituents may be bonded to any available position or combinations ofpositions on the ring. This is a particular consideration when thesubstituent is other than hydrogen.

In some embodiments of formula IV, the compound has a formula selectedfrom

With respect to formulas VII and VIII, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹,X, Y and Z are as previously defined for formula I. R¹⁰ is H, aliphatic,aryl or heterocyclyl. R¹¹, R¹² and R¹³ independently are H; aliphatic,including alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl andcycloalkynyl; halogen; heteroaliphatic; —O-aliphatic, such as alkoxy;heterocyclyl, including heteroaryl and heterocycloaliphatic; aryl;araliphatic; —O-heterocyclyl; hydroxyl; nitro; cyano; carboxyl; carboxylester; acyl; amide; amino; sulfonyl; sulfonamide; sulfanyl; sulfinyl; orhaloalkyl. In some examples, R¹⁰, R¹, R¹² and R¹³ are all H.

In some embodiments of formula V, the compound has a formula selectedfrom

With respect to formulas IX and X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, X, Yand Z are as previously defined for formula I, and R¹⁴, R¹⁵, R¹⁶, R¹⁷and R¹⁸ independently are H; aliphatic, including alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; halogen;heteroaliphatic; —O-aliphatic, such as alkoxy; heterocyclyl, includingheteroaryl and heterocycloaliphatic; aryl; araliphatic; —O-heterocyclyl;hydroxyl; nitro; cyano; carboxyl; carboxyl ester; acyl; amide; amino;sulfonyl; sulfonamide; sulfanyl; sulfinyl; or haloalkyl.

In some embodiments of formula IX, R¹⁴ is alkyl, and may be lower alkyl,particularly C₁₋₆ alkyl, such as methyl. In other embodiments of formulaIX, R¹⁵, R¹⁶ and R¹⁷ are H.

In some embodiments of formula X, R¹⁴ is amino, and may be NH₂. In otherembodiments of formula X, R¹⁵ is alkyl, and may be C₁-C₆alkyl such asmethyl. In certain embodiments of formula X, R¹⁵, R¹⁶ and R¹⁸ are H.

In some embodiments of formula VI, the compound has a formula XI

With respect to formula XI, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, X, Y and Zare as previously defined for formula I. R¹⁹, R²⁰, R²¹ and R²²independently are H; aliphatic, including alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl and cycloalkynyl; halogen; heteroaliphatic;—O-aliphatic, such as alkoxy; heterocyclyl, including heteroaryl andheterocycloaliphatic; aryl; araliphatic; —O-heterocyclyl; hydroxyl;nitro; cyano; carboxyl; carboxyl ester; acyl; amide; amino; sulfonyl;sulfonamide; sulfanyl; sulfinyl; or haloalkyl. R²³ is H, aliphatic, arylor heterocyclyl. In some embodiments of formula XI, R¹⁹, R²⁰, R²¹, R²²and R²³ are H.

In some embodiments of formula II, the compound has a formula selectedfrom

In some embodiments of formula III, the compound has a formula selectedfrom

With respect to formulas XII to XXXI, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²² and R²³are as previously described for formulas I to XI. In some examples, R³,R⁴, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²²and/or R²³ are H, and/or, R¹⁴ is H, alkyl, such as methyl, or amino,such as —NH₂.

In some embodiments of formulas I-XXXI, R³, R⁴, R⁶ and/or R⁷ are H.

Exemplary compounds according to formula I include, without limitation,the compounds in the table below and or pharmaceutically acceptablesalts thereof:

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55Exemplary compounds according to formula I include, without limitation,the compounds listed below and pharmaceutically acceptable saltsthereof:

-   I-1:    5-(6-aminopyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)furan-2-carboxamide;-   I-2:    N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)furan-2-carboxamide;-   I-3:    N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-4:    N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;-   I-5:    5-(6-aminopyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)furan-2-carboxamide;-   I-6:    N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)furan-2-carboxamide;-   I-7:    N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-8:    N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;-   I-9:    5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)furan-2-carboxamide;-   I-10:    5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)furan-2-carboxamide;-   I-11:    2-(6-aminopyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide;-   I-12:    N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-13:    N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;-   I-14:    2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide;-   I-15:    5-(6-aminopyridin-3-yl)-N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)furan-2-carboxamide;-   I-16:    N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-17:    N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;-   I-18:    N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;-   I-19:    2-(6-aminopyridin-3-yl)-N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide;-   I-20:    N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-21:    N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;-   I-22:    N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;-   I-23:    N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-24:    N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;-   I-25:    N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-26:    N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;-   I-27:    N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-28:    N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;-   I-29:    N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-30:    N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;-   I-31:    N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-32:    N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;-   I-33:    N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;-   I-34:    2-(6-aminopyridin-3-yl)-N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide;-   I-35:    N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-36:    N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;-   I-37:    N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;-   I-38:    N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-39:    N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;-   I-40:    N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-41:    N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;-   I-42:    N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-43:    N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;-   I-44:    N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-45:    N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;-   I-46:    N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-47:    N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-48:    N-(2,5-dimorpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-49:    N-(2,5-dimorpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-50:    N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-51:    N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-52:    N-(2-((2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-53:    N-(2-(methyl(2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-54:    N-(2-(methyl(2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;    or-   I-55:    N-(2-((2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide.

B. Synthesis

Disclosed benzazole compounds can be prepared as exemplified below, andas will be understood by a person of ordinary skill in the art inorganic synthesis. An exemplary synthesis may include the followingfirst reaction step according to Scheme 1:

Aniline 2 is reacted with CS2 in the presence of a base to formbenzazole 4. X is typically oxygen or sulfur, and LG¹ is a leavinggroup. Suitable leaving groups include, but are not limited to,fluoride, chloride, bromide, iodide, mesylate or tosylate. The reactionis performed in a suitable solvent, such as a polar solvent. Suitablesolvents include, but are not limited to, alcohols, such as methanol,ethanol, propanol, isopropanol or combinations thereof. The base can beany base that facilitates the reaction. Exemplary bases include, but arenot limited to, hydroxides, particularly metal hydroxides, such aspotassium hydroxide, sodium hydroxide, and lithium hydroxide. Thereaction is performed at a temperature suitable to facilitate thereaction. A suitable reaction is typically from 50° C. to 100° C.

A second reaction step in the exemplary synthesis is provided belowaccording to Scheme 2:

Benzazole 4 is reacted with amine 6 to form compound 8. The reaction isperformed in a solvent suitable to facilitate the reaction. Suitablesolvents include aprotic solvents, such as dioxane. The reaction istypically heated to a temperature suitable to facilitate the reaction,such as from 60° C. to 100° C.

A third reaction step in the exemplary synthesis is provided belowaccording to Scheme 3:

Compound 8 is reacted with a nitrating agent and/or mixture to formcompound 10. Suitable nitrating agents and/or mixtures include, but arenot limited to, nitric acid such as fuming nitric acid, fuming nitricacid/sulfuric acid or nitric acid/acetic anhydride.

A fourth reaction step in the exemplary synthesis is provided belowaccording to Scheme 4:

Compound 10 is reacted with amine 12 to form compound 14. The reactionis performed in a solvent suitable to facilitate the reaction. Suitablesolvents include aprotic solvents, such as dioxane or acetonitrile. Thereaction may be performed in the presence of a base, such as potassiumcarbonate, sodium carbonate, triethylamine or diisopropylethylamine(DIEA). Alternatively, excess amine may be used as the base, such as byusing two or more molar equivalents of amine 12 in the reaction. Thereaction is typically heated to a temperature suitable to facilitate thereaction, such as from 75° C. to 120° C.

A fifth reaction step in the exemplary synthesis is provided belowaccording to Scheme 5:

The nitro-functional group on compound 14 is reduced to form compound16. Any suitable reducing agent can be used, such as H₂/palladium oncarbon, H₂/platinum (IV) oxide, H₂/Raney nickel, Fe/HCl, Fe/acetic acid,zinc/acid, zinc/ammonium chloride, or tin chloride. The reaction isperformed in a suitable solvent, such as alcohol, including methanol,ethanol, propanol, or isopropanol; acetic acid; water; or a combinationthereof. A person of ordinary skill in the art will appreciate thatcompound 16 may form as a free base or a salt, such as an HCl salt oracetic acid salt, depending on the method used to reduce the nitrogroup.

A sixth reaction step in the exemplary synthesis is provided belowaccording to Scheme 6:

Compound 16 is reacted with carboxylic acid 18 to form compound 20. Y isoxygen or sulfur and Z is nitrogen or CR, where R is typically H oraliphatic. The carboxylic acid 18 is activated by any suitable methodand then reacted with the amine on compound 16. Suitable activationmethods include, but are not limited to: forming the acid chloride bytreatment with thionyl chloride; by treatment with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) and a base such asdiisopropylethylamine (DIEA); by treatment with carbonyldiimidazole(CDI); or by treatment with a carbodiimide, such asdicyclohexylcarbodiimide (DCC) or1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). The reaction isperformed in a solvent suitable to facilitate the reaction. Suitablesolvents include, but are not limited to, chloroform, dichloromethane,dioxane, toluene, acetonitrile, DMF, tetrahydrofuran, or a combinationthereof.

A seventh reaction step in the exemplary synthesis is provided belowaccording to Scheme 7:

Compound 20 is coupled with compound 22 to form compound 24 using anycoupling reaction suitable to form a bond between two rings. In theexample above, a boronic acid coupling is shown, where the leaving groupLG² on compound 20 is halo, such as bromo or iodo. Other suitablecoupling functional groups include trialkyl tin or boronic esters, suchas a boronic acid pinacol ester. The coupling reaction typicallyproceeds in the presence of a suitable catalyst. For a boronic acidcoupling, the catalyst typically is a palladium catalyst, such asPdCl₂(dppf)₂, palladium acetate and triphenyl phosphine, ortetrakis(triphenylphosphine)palladium(0). The reaction is performed inthe presence of a base, such as metal carbonates, including sodium,potassium or cesium carbonate, and is performed in a suitable solvent orsolvent mixture, such as dioxane/water or DME/ethanol/water. Thereaction may be heated at a suitable temperature, such as from 50° C. to140° C., typically about 120° C., and/or agitated for a suitable periodof time, such as from 1 hour to 3 days, from 6 hours to 24 hours, orfrom 12 hours to 18 hours, to facilitate the reaction proceeding tocompletion. The reaction may be performed in a microwave, whichtypically reduces the reaction time. Compound 24 is then isolated fromthe reaction mixture and purified by a suitable technique.

C. Additional Therapeutic Agents for Combination

The compounds of the present invention may be used alone, in combinationwith one another, or as an adjunct to, or in combination with, otherestablished therapies. In another aspect, the compounds of the presentinvention may be used in combination with other therapeutic agentsuseful for the disorder or condition being treated. These compounds maybe administered simultaneously or sequentially in any order. Thecompounds may be administered within a time period such that a subjectexperiences an overlapping beneficial effect from both the benzazolecompound and the additional therapeutic agent(s). The benzazole compoundand the additional therapeutic agent(s) may be administered by the sameroute of administration, or by a different route. It is specificallyintended that the present compounds be administered in combination withone or more additional therapeutic agents, including in combination withone or more agents described in this section.

In some embodiments, the second therapeutic agent is an analgesic, anantibiotic, an anticoagulant, an antibody, an anti-inflammatory agent,an immunosuppressant, a guanylate cyclase-C agonist, an intestinalsecretagogue, an antiviral, anticancer, antifungal, or a combinationthereof. The anti-inflammatory agent may be a steroid or a nonsteroidalanti-inflammatory agent. In certain embodiments, the nonsteroidalanti-inflammatory agent is selected from aminosalicylates,cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen,flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin,meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen,oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combinationthereof. In some embodiments, the immunosuppressant is mercaptopurine, acorticosteroid, an alkylating agent, a calcineurin inhibitor, an inosinemonophosphate dehydrogenase inhibitor, antilymphocyte globulin,antithymocyte globulin, an anti-T-cell antibody, or a combinationthereof. In one embodiment, the antibody is infliximab.

In some embodiments, the present compounds may be used with otheranti-cancer or cytotoxic agents. Various classes of anti-cancer andanti-neoplastic compounds for use with the presently disclosedinhibitors include, but are not limited to, alkylating agents,antimetabolites, vinca alkyloids, taxanes, antibiotics, enzymes,cytokines, platinum coordination complexes, substituted ureas, kinaseinhibitors, hormones and hormone antagonists and hypomethylating agents,for example DNMT inhibitors, such as azacitidine and decitabine.Exemplary alkylating agents include, without limitation,mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil,ethyleneimines, methylmelamines, alkyl sulfonates (e.g., busulfan), andcarmustine. Exemplary antimetabolites include, by way of example and notlimitation, folic acid analog methotrexate; pyrmidine analogfluorouracil, cytosine arbinoside; purine analogs mercaptopurine,thioguanine, and azathioprine. Exemplary vinca alkyloids include, by wayof example and not limitation, vinblastine, vincristine, paclitaxel, andcolchicine. Exemplary antibiotics include, by way of example and notlimitation, actinomycin D, daunorubicin, and bleomycin. An exemplaryenzyme effective as an anti-neoplastic agent includes L-asparaginase.Exemplary coordination compounds include, by way of example and notlimitation, cisplatin and carboplatin.

Exemplary hormones and hormone related compounds include, by way ofexample and not limitation, adrenocorticosteroids prednisone anddexamethasone; aromatase inhibitors amino glutethimide, formestane, andanastrozole; progestin compounds hydroxyprogesteron caproate,medroxyprogesterone; and anti-estrogen compound tamoxifen.

Other chemotherapeutic agents for combination include immunooncologyagents, such as anti-PD-1 and/or anti-PD-L1 antibodies, such asnivolumab, pembrolizumab, lambrolizumab, pidilizumab, BMS-936559,MPDL3280A, AMP-224 or MEDI4736; anti-CTLA-4 antibodies, such asipilimumab or tremelimumab; anti-KIR antibodies, such as lirilumab;anti-LAG3 antibodies, such as BMS-986016; anti-CD137 antibodies, such asurelumab; anti-SLAM antibodies, such as anti-SLAMF7 for exampleelotuzumab; PI3K inhibitors, such as idelalisib, AZD8186, INCB40093 andINCB50465; and indole dioxygenase (IDO) and/or tryptophan dioxygenaseinhibitors (TDO), such as 1-methyltryptophan, indoximod, NSC 36398(dihydroquercetin, taxifolin), NLG919, INCB024360 (epacodostat), andF001287. In particular embodiments, two or more immunooncology agentsare combined with a disclosed benzazole compound. Typically, theimmunooncology agents in such combinations act on different targets. Forexample, the combination of an anti-PD-1 agent, such as nivolumab withan anti-CTLA-4 agent, such as ipilimumab, is particularly useful incombination with a benzazole compound.

In some embodiments, the benzazole compound may be used in combinationwith an immunooncology agent and/or with other anti-cancer or cytotoxicagents. In particular embodiments, the present compounds are combinedwith an immunooncology agent and are further combined with one or moreagents from the current standard of care for a given malignancy. Thefollowing table displays exemplary cancers treatable in the combinationtherapies comprising the presently disclosed benzazole compounds andlists additional treatments for use in combination with the benzazolecompounds and immunooncology agent disclosed herein:

Cancer Drug or Treatment Glioma lomustine, temozolide and/or radiationhepatocellular carcinoma sorafenib, regorafenib myelodysplasticsyndromes decitabine or azacytidine pancreatic cancer Gemcitabineovarian cancer, such as epithelial carboplatin, cisplatin, doxorubicin,ovarian carcinoma gemcitabine, paclitaxel breast cancer Trastuzumabbasal and squamous 5-fluorouracil, imiquimod, skin carcinomasphotodynamic therapy (e.g. with 5- aminolevulinic acid), head and neckcarcinoma bleomycin, cisplatin, cetuximab, docetaxel, fluorouracil,methotrexate triple negative breast cancer Paclitaxel Prostateabiraterone, enzalutamide

These and other useful anti-cancer compounds are described in MerckIndex, 13th Ed. (O'Neil M. J. et al., ed) Merck Publishing Group (2001)and Goodman and Gilmans The Pharmacological Basis of Therapeutics, 10thEdition, Hardman, J. G. and Limbird, L. E. eds., pg. 1381-1287, McGrawHill, (1996), both of which are incorporated by reference herein.

Among the CTLA 4 antibodies that can be used in combination with thepresently disclosed inhbitors is ipilimumab, marketed as YERVOY® byBristol-Myers Squibb.

Additional anti-proliferative compounds useful in combination with thecompounds of the present invention include, by way of example and notlimitation, antibodies directed against growth factor receptors (e.g.,anti-Her2); and cytokines such as interferon-α and interferon-γ,interleukin-2, and GM-CSF.

In particular embodiments, including the treatment of leukemias,including CLL, mantle cell lymphoma and ALL, the presently disclosedcompounds are used in combination with a B-cell lymphoma 2 (BCL2)inhibitor, such as ABT-199 or ABT737.

Examples of kinase inhibitors that are useful in combination with thepresently disclosed compounds, particularly in treating malignanciesinclude, Btk inhibitors, such as ibrutinib; CDK inhibitors, such aspalbociclib; EGFR inhibitors, such as afatinib, erlotinib, gefitinib,lapatinib and vandetinib; Mek inhibitors, such as trametinib; Rafinhibitors, such as dabrafenib, sorafenib and vemurafenib; VEGFRinhibitors, such as axitinib, lenvatinib, nintedanib, and pazopanib;BCR-Abl inhibitors, such as bosutinib, dasatinib, imatinib andnilotinib; PI3-kinase inhibitors, such as idelalisib; Syk inhibitors,such as fostamatinib; and JAK inhibitors, such as baricitinib,ruxolitinib and tofacitinib. In other embodiments, the second oradditional therapeutic agent or agents for combination with thepresently disclosed inhibitors may be selected from any of thefollowing:

analgesics—morphine, fentanyl, hydromorphone, oxycodone, codeine,acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine,flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

antibiotics—aminoglycosides (e.g., amikacin, gentamicin, kanamycin,neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g.,ertapenem, doripenem, imipenem, cilastatin, and meropenem),cephalosporins (e.g., cefadroxil, cefazolin, cefalotin, cephalexin,cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime,cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, andcefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, andtelavancin), lincosamides (e.g., clindamycin and incomysin),lipopeptides) e.g., daptomycin), macrolides (azithromycin,clarithromycin, dirithromycin, erythromycin, roxithromycin,troleandomycin, telithromycin, and spectinomycin), monobactams (e.g.,aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin),penicilllins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin,cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, piperacillin,temocillin, and ticarcillin), penicillin combinations (e.g.,amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam,and ticarcillin/clavulanate), polypeptides (e.g., bacitracin, colistin,and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin,gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid,norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, andtemafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine,sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole,sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole,trimethoprim, and trimethoprim-sulfamethoxaxzole), tetracyclines (e.g.,demeclocycline, doxycycline, minocycline, oxytetracycline, andtetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone,capreomycin, cycloserine, ethambutol, ethionamide, isoniazid,pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, andstreptomycin), and others, such as arsphenamine, chloramphenicol,fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin,platensimycin, quinuprisin/dalfopristin, rifaximin, thiamphenicol,tigecycline, and timidazole;

antibodies—anti-TNF-α antibodies, e.g., infliximab (Remicade™),adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g.,rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1antibodies, e.g., anakinra; anti PD-1 and/or anti-PD-L1 antibodies, e.g.nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224,MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab,clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab,sarilumab, secukinumab, toralizumab, zanolimumab;

anticoagulants—warfarin (Coumadin™), acenocoumarol, phenprocoumon,atromentin, phenindione, heparin, fondaparinux, idraparinux,rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam,dabigatran, ximelagatran, batroxobin, hementin;

anti-inflammatory agents—steroids, e.g., budesonide, nonsteroidalanti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine,mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors(COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac,famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen,indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone,naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

immunosuppressants—mercaptopurine, corticosteroids such asdexamethasone, hydrocortisone, prednisone, methylprednisolone andprednisolone, alkylating agents such as cyclophosphamide, calcineurininhibitors such as cyclosporine, sirolimus and tacrolimus, inhibitors ofinosine monophosphate dehydrogenase (IMPDH) such as mycophenolate,mycophenolate mofetil and azathioprine, and agents designed to suppresscellular immunity while leaving the recipient's humoral immunologicresponse intact, including various antibodies (for example,antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonalanti-T-cell antibodies (OKT3)) and irradiation. Azathioprine iscurrently available from Salix Pharmaceuticals, Inc. under the brandname Azasan; mercaptopurine is currently available from GatePharmaceuticals, Inc. under the brand name Purinethol; prednisone andprednisolone are currently available from Roxane Laboratories, Inc.;Methyl prednisolone is currently available from Pfizer; sirolimus(rapamycin) is currently available from Wyeth-Ayerst under the brandname Rapamune; tacrolimus is currently available from Fujisawa under thebrand name Prograf; cyclosporine is current available from Novartisunder the brand name Sandimmune and Abbott under the brand name Gengraf;IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid arecurrently available from Roche under the brand name Cellcept andNovartis under the brand name Myfortic; azathioprine is currentlyavailable from Glaxo Smith Kline under the brand name Imuran; andantibodies are currently available from Ortho Biotech under the brandname Orthoclone, Novartis under the brand name Simulect (basiliximab)and Roche under the brand name Zenapax (daclizumab); and

Guanylate cyclase—C receptor agonists or intestinal secretagogues, forexample linaclotide, sold under the name Linzess.

These various agents can be used in accordance with their standard orcommon dosages, as specified in the prescribing information accompanyingcommercially available forms of the drugs (see also, the prescribinginformation in the 2006 Edition of The Physician's Desk Reference), thedisclosures of which are incorporated herein by reference.

D. Compositions Comprising Benzazole Compounds

The disclosed benzazole compounds may be used alone, in any combination,and in combination with, or adjunctive to, at least one secondtherapeutic agent, and further the benzazole compounds, and the at leastone second therapeutic, may be used in combination with any suitableadditive useful for forming compositions for administration to asubject. Additives can be included in pharmaceutical compositions for avariety of purposes, such as to dilute a composition for delivery to asubject, to facilitate processing of the formulation, to provideadvantageous material properties to the formulation, to facilitatedispersion from a delivery device, to stabilize the formulation (e.g.,antioxidants or buffers), to provide a pleasant or palatable taste orconsistency to the formulation, or the like. Typical additives include,by way of example and without limitation: pharmaceutically acceptableexcipients; pharmaceutically acceptable carriers; and/or adjuvants, suchas mono-, di-, and polysaccharides, sugar alcohols and other polyols,such as, lactose, glucose, raffinose, melezitose, lactitol, maltitol,trehalose, sucrose, mannitol, starch, or combinations thereof;surfactants, such as sorbitols, diphosphatidyl choline, and lecithin;bulking agents; buffers, such as phosphate and citrate buffers;anti-adherents, such as magnesium stearate; binders, such as saccharides(including disaccharides, such as sucrose and lactose,), polysaccharides(such as starches, cellulose, microcrystalline cellulose, celluloseethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers(such as polyvinylpyrrolidone, polyalkylene gylcols); coatings (such ascellulose ethers, including hydroxypropylmethyl cellulose, shellac, cornprotein zein, and gelatin); release aids (such as enteric coatings);disintegrants (such as crospovidone, crosslinked sodium carboxymethylcellulose, and sodium starch glycolate); fillers (such as dibasiccalcium phosphate, vegetable fats and oils, lactose, sucrose, glucose,mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavorsand sweeteners (such as mint, cherry, anise, peach, apricot or licorice,raspberry, and vanilla; lubricants (such as minerals, exemplified bytalc or silica, fats, exemplified by vegetable stearin, magnesiumstearate or stearic acid); preservatives (such as antioxidantsexemplified by vitamin A, vitamin E, vitamin C, retinyl palmitate, andselenium, amino acids, exemplified by cysteine and methionine, citricacid and sodium citrate, parabens, exemplified by methyl paraben andpropyl paraben); colorants; compression aids; emulsifying agents;encapsulation agents; gums; granulation agents; and combinationsthereof.

III. Methods of Use

A. Diseases/Disorders

The disclosed benzazole compounds, as well as combinations and/orcompositions thereof, may be used to ameliorate, treat or prevent avariety of diseases and/or disorders. In particular embodiments, thebenzazole compound, combinations of benzazole compounds, or compositionsthereof, may be used to treat or prevent auto-immune diseases,inflammatory disorders, cardiovascular diseases, nerve disorders,neurodegenerative disorders, allergic disorders, asthma, pancreatitis,multi-organ failure, kidney diseases, platelet aggregation, cancer,transplantation, sperm motility, erythrocyte deficiency, graftrejection, lung injuries, respiratory diseases, ischemic conditions,bacterial infections and/or viral infections.

In some embodiments, the benzazole compound, combinations of benzazolecompounds, or compositions thereof, may be used to treat or preventallergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupuserythematosus, rheumatoid arthritis, type I diabetes mellitus,inflammatory bowel disease, biliary cirrhosis, uveitis, multiplesclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid,sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis,ichthyosis, Graves ophthalmopathy or asthma.

The benzazole compound, combinations of benzazole compounds, orcompositions thereof, may also be useful for ameliorating, treating orpreventing immune regulatory disorders related to bone marrow or organtransplant rejection or graft-versus-host disease. Examples ofinflammatory and immune regulatory disorders that can be treated withthe present compounds include, but are not limited to, transplantationof organs or tissue, graft-versus-host diseases brought about bytransplantation, autoimmune syndromes including rheumatoid arthritis,systemic lupus erythematosus, Hashimoto's thyroiditis, multiplesclerosis, systemic sclerosis, myasthenia gravis, type I diabetes,uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, postinfectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichenplanus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupuserythematosus, acne, alopecia areata, keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns, coeliac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerativecolitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy,multiple myositis, Guillain-Barre syndrome, Meniere's disease,polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjögren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenesis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, partial liver resection,acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock,or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic liver disease, including alcoholic cirrhosis, non-alcoholicsteatohepatitis (NASH), hepatic failure, fulminant hepatic failure,late-onset hepatic failure, “acute-on-chronic” liver failure,augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMVinfection, AIDS, cancer, senile dementia, Parkinson's disease, trauma,or chronic bacterial infection.

In certain embodiments the present compounds are useful for treatingnerve disorders. For example, the present compounds can be used to treatnerve pain, including neuropathic pain and inflammation induced pain.

In certain embodiments, the benzazole compound, combinations ofbenzazole compounds, or compositions thereof, are useful for treatingand/or preventing alcoholic liver disease (steatohepatitis), rheumatoidarthritis, psoriatic arthritis, osteoarthritis, systemic lupuserythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis,systemic sclerosis, multiple sclerosis, psoriasis, in particularpustular psoriasis, type I diabetes, type II diabetes, inflammatorybowel disease (including Crohn's disease and ulcerative colitis),hyperimmunoglobulinemia d and periodic fever syndrome,cryopyrin-associated periodic syndromes, Schnitzler's syndrome, systemicjuvenile idiopathic arthritis, adult's onset Still's disease, gout,pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke,atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptorantagonist), Alzheimer's disease, Parkinson's disease.

Proliferative diseases that may be treated by the benzazole compound,combinations of benzazole compounds, or compositions thereof, includebenign or malignant tumors, solid tumors and liquid tumors, includingcarcinoma of the brain, kidney, liver, adrenal gland, bladder, breast,head and neck, stomach, gastric tumors, ovaries, colon, rectum,prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract,esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas,neuroblastomas, multiple myeloma, gastrointestinal cancer, especiallycolon carcinoma or colorectal adenoma, a tumor of the neck and head, anepidermal hyperproliferation, psoriasis, prostate hyperplasia, aneoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, a MyD88driven disorder (such as ABC diffuse large B-cell lymphoma (DLBCL),Waldenstrim's macroglobulinemia, Hodgkin's lymphoma, primary cutaneousT-cell lymphoma or chronic lymphocytic leukemia), pleural effusionlymphoma, smoldering or indolent multiple myeloma, or hematologicalmalignancies (including leukemia, DLBCL, ABC DLBCL, chronic lymphocyticleukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma,Burkitt lymphomalleukemia, acute lymphocytic leukemia (ALL), B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplasticsyndrome, myelofibrosis, polycythemia vera, Kaposi's sarcoma,Waldenstrim's macroglobulinemia (WM), splenic marginal zone lymphoma,multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). Inparticular, the presently disclosed compounds are useful in treatingdrug resistant malignancies, such as those resistant to JAK inhibitors,those resistant to IRAK inhibitors, ibrutinib resistant malignancies,including ibrutinib resistant hematological malignancies, such asibrutinib resistant CLL and ibrutinib resistant Waldenstrim'smacroglobulinemia.

Examples of allergic disorders that may be treated using the benzazolecompound, combinations of benzazole compounds, or compositions thereof,include, but are not limited to, asthma (e.g. atopic asthma, allergicasthma, atopic bronchial IgE-mediated asthma, non-atopic asthma,bronchial asthma, non-allergic asthma, essential asthma, true asthma,intrinsic asthma caused by pathophysiologic disturbances, essentialasthma of unknown or unapparent cause, emphysematous asthma,exercise-induced asthma, emotion-induced asthma, extrinsic asthma causedby environmental factors, cold air induced asthma, occupational asthma,infective asthma caused by or associated with bacterial, fungal,protozoal, or viral infection, incipient asthma, wheezy infant syndrome,bronchiolitis, cough variant asthma or drug-induced asthma), allergicbronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennialallergic rhinitis, perennial rhinitis, vasomotor rhinitis, post-nasaldrip, purulent or non-purulent sinusitis, acute or chronic sinusitis,and ethmoid, frontal, maxillary, or sphenoid sinusitis.

As another example, rheumatoid arthritis (RA) typically results inswelling, pain, loss of motion and tenderness of target jointsthroughout the body. RA is characterized by chronically inflamedsynovium that is densely crowded with lymphocytes. The synovialmembrane, which is typically one cell layer thick, becomes intenselycellular and assumes a form similar to lymphoid tissue, includingdendritic cells, T-, B- and NK cells, macrophages and clusters of plasmacells. This process, as well as a plethora of immunopathologicalmechanisms including the formation of antigen-immunoglobulin complexes,eventually result in destruction of the integrity of the joint,resulting in deformity, permanent loss of function and/or bone erosionat or near the joint. The benzazole compound, combinations of benzazolecompounds, or compositions thereof, may be used to treat, ameliorate orprevent any one, several or all of these symptoms of RA. Thus, in thecontext of RA, the compounds are considered to provide therapeuticbenefit when a reduction or amelioration of any of the symptoms commonlyassociated with RA is achieved, regardless of whether the treatmentresults in a concomitant treatment of the underlying RA and/or areduction in the amount of circulating rheumatoid factor (“RF”).

The American College of Rheumatology (ACR) has developed criteria fordefining improvement and clinical remission in RA. Once such parameter,the ACR20 (ACR criteria for 20% clinical improvement), requires a 20%improvement in the tender and swollen joint count, as well as a 20%improvement in 3 of the following 5 parameters: patient's globalassessment, physician's global assessment, patient's assessment of pain,degree of disability, and level of acute phase reactant. These criteriahave been expanded for 50% and 70% improvement in ACR50 and ACR70,respectively. Other criteria include Paulu's criteria and radiographicprogression (e.g. Sharp score).

In some embodiments, therapeutic benefit in patients suffering from RAis achieved when the patient exhibits an ACR20. In specific embodiments,ACR improvements of ACRC50 or even ACR70 may be achieved.

B. Formulations and Administration

Pharmaceutical compositions comprising the disclosed compounds (orprodrugs thereof) may be manufactured by conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilization processes. The compositionsmay be formulated in conventional manner using one or morephysiologically acceptable excipients, diluents, carriers, adjuvants orauxiliaries to provide preparations which can be used pharmaceutically.

The active compound or prodrug may be formulated in the pharmaceuticalcompositions per se, or in the form of a hydrate, solvate, N-oxide orpharmaceutically acceptable salt. Typically, such salts are more solublein aqueous solutions than the corresponding free acids and bases, butsalts having lower solubility than the corresponding free acids andbases may also be formed.

Pharmaceutical compositions of the invention may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, such as i.v.or i.p., transdermal, rectal, vaginal, etc., or a form suitable foradministration by inhalation or insufflation.

For topical administration, the active compound(s), hydrate, solvate,N-oxide or pharmaceutically acceptable salt or prodrug(s) may beformulated as solutions, gels, ointments, creams, suspensions, etc. asare well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile, pyrogen-free water, buffer, dextrose solution, etc., beforeuse. To this end, the active compound(s) maybe dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients, such as:binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); and/or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such as:suspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™. or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases, such as cocoabutter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s), hydrate, solvate, N-oxide,pharmaceutically acceptable salt or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5 20mg/ml); benzalkonium chloride (0.1 0.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5 5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1 15 mg/ml); phenylethanol (1 4 mg/ml); and dextrose (20 50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH 5 to pH 7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation contains 20 mg/mLcompound or prodrug, 1% (v/v) Polysorbate 80 (TWEEN® 80), 50 mM citrateand/or 0.9% sodium chloride.

For ocular administration, the active compound(s) or prodrug(s) may beformulated as a solution, emulsion, suspension, etc. suitable foradministration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. Nos. 6,261,547;6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222;5,403,841; 5,077,033; 4,882,150; and 4,738,851, which are incorporatedherein by reference.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient maybe formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. Nos. 5,407,713;5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189;5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which areincorporated herein by reference.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s) or prodrug(s). Certainorganic solvents, such as dimethylsulfoxide (DMSO), may also beemployed, although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

C. Dosages

The benzazole compound or combinations of benzazole compounds willgenerally be used in an amount effective to achieve the intended result,for example, in an amount effective to treat or prevent a particularcondition. The benzazole compound(s), or compositions thereof, can beadministered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. Therapeutic benefitmeans eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering from anallergy provides therapeutic benefit not only when the underlyingallergic response is eradicated or ameliorated, but also when thepatient reports a decrease in the severity or duration of the symptomsassociated with the allergy following exposure to the allergen. Asanother example, therapeutic benefit in the context of asthma includesan improvement in respiration following the onset of an asthmatic attackor a reduction in the frequency or severity of asthmatic episodes.Therapeutic benefit also includes halting or slowing the progression ofthe disease, regardless of whether improvement is realized.

As known by those of ordinary skill in the art, the preferred dosage ofbenzazole compounds will also depend on various factors, including theage, weight, general health, and severity of the condition of thepatient or subject being treated. Dosage may also need to be tailored tothe sex of the individual and/or the lung capacity of the individual,when administered by inhalation. Dosage may also be tailored toindividuals suffering from more than one condition or those individualswho have additional conditions that affect lung capacity and the abilityto breathe normally, for example, emphysema, bronchitis, pneumonia, andrespiratory infections. Dosage, and frequency of administration of thebenzazole compound(s) or compositions thereof, will also depend onwhether the benzazole compound(s) are formulated for treatment of acuteepisodes of a condition or for the prophylactic treatment of a disorder.A person or ordinary skill in the art will be able to determine theoptimal dose for a particular individual.

For prophylactic administration, the benzazole compound, combinations ofbenzazole compounds, or compositions thereof, can be administered to apatient or subject at risk of developing one of the previously describedconditions. For example, if it is unknown whether a patient or subjectis allergic to a particular drug, the benzazole compound, combinationsof benzazole compounds, or compositions thereof, can be administeredprior to administration of the drug to avoid or ameliorate an allergicresponse to the drug. Alternatively, prophylactic administration can beused to avoid or ameliorate the onset of symptoms in a patient diagnosedwith the underlying disorder. For example, a benzazole compound(s), orcomposition thereof, can be administered to an allergy sufferer prior toexpected exposure to the allergen. A benzazole compound, combinations ofbenzazole compounds, or compositions thereof, can also be administeredprophylactically to healthy individuals who are repeatedly exposed toagents known to one of the above-described maladies to prevent the onsetof the disorder. For example, a benzazole compound, combinations ofbenzazole compounds, or compositions thereof, can be administered to ahealthy individual who is repeatedly exposed to an allergen known toinduce allergies, such as latex, in an effort to prevent the individualfrom developing an allergy. Alternatively, a benzazole compound,combinations of benzazole compounds, or compositions thereof, can beadministered to a patient suffering from asthma prior to partaking inactivities which trigger asthma attacks to lessen the severity of, oravoid altogether, an asthmatic episode.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in subjects can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ or EC₅₀ of the particular compound asmeasured in an in vitro assay. Dosages can be calculated to achieve suchcirculating blood or serum concentrations taking into account thebioavailability of the particular compound. Fingl & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pages 1-46, Pergamon Press, and the referencescited therein, provide additional guidance concerning effective dosages.

In some embodiments, the disclosed compounds have an EC₅₀ from greaterthan 0 to 20 μM, such as from greater than 0 to 10 μM, from greater than0 to 5 μM, from greater than 0 to 1 μM, from greater than 0 to 0.5 μM,or from greater than 0 to 0.1 μM.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, (1995) Allergy 50(21Suppl):6-9,discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Persons of ordinary skill in the art can adapt such information todetermine dosages suitable for human administration.

Dosage amounts of disclosed benzazole compounds will typically be in therange of from greater than 0 mg/kg/day, such as 0.0001 mg/kg/day or0.001 mg/kg/day or 0.01 mg/kg/day, up to at least 100 mg/kg/day. Moretypically, the dosage (or effective amount) may range from 0.0025 mg/kgto about 1 mg/kg administered at least once per day, such as from 0.01mg/kg to 0.5 mg/kg or from 0.05 mg/kg to 0.15 mg/kg. The total dailydosage typically ranges from 0.1 mg/kg to 5 mg/kg or to 20 mg/kg perday, such as from 0.5 mg/kg to 10 mg/kg per day or from 0.7 mg/kg perday to 2.5 mg/kg/day. Dosage amounts can be higher or lower dependingupon, among other factors, the activity of the benzazole compound, itsbioavailability, the mode of administration, and various factorsdiscussed above.

Dosage amount and dosage interval can be adjusted for individuals toprovide plasma levels of the benzazole compound that are sufficient tomaintain therapeutic or prophylactic effect. For example, the compoundscan be administered once per day, multiple times per day, once per week,multiple times per week (e.g., every other day), one per month, multipletimes per month, or once per year, depending upon, amongst other things,the mode of administration, the specific indication being treated, andthe judgment of the prescribing physician. Persons of ordinary skill inthe art will be able to optimize effective local dosages without undueexperimentation.

Compositions comprising one or more of the disclosed benzazole compoundstypically comprise from greater than 0 up to 99% of the benzazolecompound, or compounds, and/or other therapeutic agent by total weightpercent. More typically, compositions comprising one or more of thedisclosed benzazole compounds comprise from 1 to 20 total weight percentof the benzazole compound and other therapeutic agent, and from 80 to 99weight percent of a pharmaceutically acceptable additive.

Preferably, the benzazole compound, combinations of benzazole compounds,or compositions thereof, will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of the benzazolecompound can be determined using standard pharmaceutical procedures. Thedose ratio between toxic and therapeutic (or prophylactic) effect is thetherapeutic index. Benzazole compounds that exhibit high therapeuticindices are preferred.

IV. Examples Example 1 Preparation of 5-fluorobenzo[d]oxazole-2-thiol

A solution of 2-amino-4-fluorophenol (10 g, 78.8 mmol), carbon disulfide(35 mL), and potassium hydroxide (5.3 g, 94.6 mmol) in ethanol (200 mL)was heated to reflux overnight. The reaction mixture was concentrated todryness then diluted with water. This solution was neutralized with 1MHCl then washed with ethyl acetate several times. The combined organicphases were washed with brine, dried over Na₂SO₄, and concentrated invacuo giving 9.3 g (70% yield) of the desired5-fluorobenzo[d]oxazole-2-thiol. ¹H NMR (300 MHz, DMSO-d₆) δ 7.51 (ddd,J=8.8, 4.2, 0.6 Hz, 1H), 7.15-7.04 (m, 2H), 3.31 (br s, 1H). LC-MS(m/z): 170.2.

Example 2 Preparation of5-fluoro-N-(2-methoxyethyl)-N-methylbenzo[d]oxazol-2-amine

A solution of 5-fluorobenzo[d]oxazole-2-thiol (1.17 g, 6.92 mmol) and(2-methoxyethyl)methylamine (3.7 mL, 34.1 mmol) in dioxane (6 mL) washeated at 85° C. overnight. The reaction was concentrated to dryness andthe resulting product,5-fluoro-N-(2-methoxyethyl)-N-methylbenzo[d]oxazol-2-amine, was usedcrude.

Example 3 Preparation of5-fluoro-N-(2-methoxyethyl)-N-methyl-6-nitrobenzo[d]oxazol-2-amine

To a solution of5-fluoro-N-(2-methoxyethyl)-N-methyl-6-nitrobenzo[d]oxazol-2-amine (6.92mmol) in H₂SOO₄ (9 mL) cooled in an ice bath was added fuming HNO₃ (600μL) dropwise. The reaction was permitted to warm to room temperaturethen gently heated at 35° C. overnight. The reaction was complete whenmonitored by LC-MS and allowed to cool to room temperature. The reactionmixture was then poured over ice and made basic by addition of 4M NaOHto pH 9. The solid formed was filtered and dried giving the desiredproductN-(2-methoxyethyl)-N-methyl-6-nitro-5-(piperidin-1-yl)benzo[d]oxazol-2-amine(1.25 g, 4.62 mmol) in a 67% yield.

Example 4 Preparation ofN-(2-methoxyethyl)-N-methyl-6-nitro-5-(piperidin-1-yl)benzo[d]oxazol-2-amine

A solution of5-fluoro-N-(2-methoxyethyl)-N-methyl-6-nitrobenzo[d]oxazol-2-amine (1.24g, 4.63 mmol), piperidine (915 μL, 9.26 mmol) in dioxane (40 mL) washeated at 95° C. for 5 hours. Upon cooling to room temperature, thereaction was concentrated in vacuo and purified by Si gel chromatographyeluting with 0-90% ethyl acetate in hexanes. The desiredN-(2-methoxyethyl)-N-methyl-6-nitro-5-(piperidin-1-yl)benzo[d]oxazol-2-amineproduct eluted at 35% EtOAc/Hex giving 1.22 g (79% yield). LC-MS (m/z):335.3.

Example 5 Preparation ofN2-(2-methoxyethyl)-N2-methyl-5-(piperidin-1-yl)benzo[d]oxazole-2,6-diaminehydrochloride

To a solution ofN-(2-methoxyethyl)-N-methyl-6-nitro-5-(piperidin-1-yl)benzo[d]oxazol-2-amine(1.22 g, 3.65 mmol) and concentrated hydrochloric acid (600 μL) in water(1 mL) and ethanol (20 mL) was added iron dust (2 g, 36.5 mmol). Themixture was heated to reflux for about 1 hour, when the reaction wascomplete by LC-MS monitoring. The mixture was filtered through celite,concentrated in vacuo, and used as crude. LC-MS (m/z): 305.7.

Example 6 Preparation of2-bromo-N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide

A solution ofN2-(2-methoxyethyl)-N2-methyl-5-(piperidin-1-yl)benzo[d]oxazole-2,6-diaminehydrochloride (170 mg, 0.5 mmol), 2-Bromothiazole-4-carboxylic acid (125mg, 0.6 mmol), and N,N-diisopropylethylamine (435 μL, 2.5 mmol) inCH₂Cl₂ (5 mL) was stirred at room temperature overnight. The solutionwas concentrated in vacuo then diluted with ethyl acetate, washed withwater, saturated NaHCO₃ solution, and brine. After drying over Na₂SO₄,the solution was concentrated in vacuo and purified via Si gelchromatography eluting with 0-100% ethyl acetate in hexanes. The producteluted at 80-100% EtOAc/Hex yielding2-bromo-N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide(204 mg, 0.413 mmol, 83% yield) as a pale khaki solid. ¹H NMR (300 MHz,DMSO-d₆) δ 10.50 (s, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 7.21 (s, 1H), 3.65(t, J=5.4 Hz, 2H), 3.56 (t, J=5.4 Hz, 2H), 3.25 (s, 3H), 3.12 (s, 3H),2.82-2.75 (m, 4H), 1.77 (p, J=6.0 Hz, 4H), 1.63-1.52 (m, 2H). LC-MS(m/z): 494.8.

Example 7 Preparation ofN-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(I-51)

In a microwave vial was prepared a mixture of2-bromo-N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide(75 mg, 0.15 mmol), pyrazole-4-boronic acid pinacol ester (87 mg, 0.45mmol), and 2M Na₂CO₃ aqueous solution (225 μL, 0.45 mmol) in dioxane(3.5 mL). After purging the vessel under nitrogen gas,tetrakis(triphenylphosphine) palladium (17 mg, 0.015 mmol) and thereaction was heated in a microwave at 120° C. for 1 hour monitoring byLC-MS. The mixture was filtered through celite and the solventconcentrated. The crude reaction mixture was purified by Si gelchromatography eluting with 0-12% 2M NH₃/MeOH in CH₂Cl₂. This solid wasfurther triturated with EtOAc to yieldN-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(38 mg, 0.079 mmol, 53% yield).

¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 10.67 (s, 1H), 8.45 (s, 1H),8.41 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.22 (s, 1H), 3.65 (t, J=5.6Hz, 2H), 3.57 (t, J=5.6 Hz, 2H), 3.25 (s, 3H), 3.13 (s, 3H), 2.85-2.77(m, 4H), 1.87-1.76 (m, 4H), 1.66-1.55 (m, 2H). LC-MS (m/z): 482.6

Example 8

Compounds I-1 through I-55 were made in a similar manner as Examples 1-7above. Characterization data for compounds I-1 through I-54 are providedbelow.

I-1:5-(6-aminopyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.88 (s, 1H), 8.38 (s, 1H), 7.83 (dd, J=8.7,2.5 Hz, 1H), 7.30 (s, 1H), 7.28 (d, J=3.6 Hz, 1H), 6.91 (d, J=3.6 Hz,1H), 6.52 (d, J=8.7 Hz, 1H), 6.44 (s, 2H), 3.70 (t, J=4.9 Hz, 4H), 2.80(t, J=4.9 Hz, 4H), 1.76 (p, J=5.7 Hz, 4H), 1.58 (br s, 2H).

LCMS (m/z): 489.7 (MH⁺).

I-2:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.94 (s, 1H), 10.03 (s, 1H), 8.82 (d, J=2.1Hz, 1H), 8.44 (d, J=2.1 Hz, 1H), 8.41 (s, 1H), 7.57 (d, J=3.5 Hz, 1H),7.35 (d, J=3.6 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J=3.6 Hz, 1H), 6.47 (d,J=3.4 Hz, 1H), 3.75-3.66 (m, 4H), 3.59-3.52 (m, 4H), 2.83 (t, J=5.2 Hz,4H), 1.83 (p, J=5.8 Hz, 4H), 1.61 (br s, 2H).

LCMS (m/z): 513.8 (MH⁺).

I-3:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (s, 1H), 9.79 (s, 1H), 8.36 (s, 1H),8.17 (s, 1H), 7.90 (s, 1H), 7.28 (s, 1H), 7.27 (d, J=3.6 Hz, 1H), 6.77(d, J=3.6 Hz, 1H), 3.73-3.67 (m, 4H), 3.58-3.51 (m, 4H), 2.84-2.77 (m,4H), 1.77 (p, J=5.8 Hz, 4H), 1.59 (br s, 2H).

LCMS (m/z): 463.7 (MH⁺).

I-4:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.21 (s, 1H), 9.92 (s, 1H), 8.38 (s, 1H),7.89 (dd, J=2.4, 1.4 Hz, 1H), 7.30 (d, J=3.6 Hz, 1H), 7.29 (s, 1H), 6.91(d, J=3.6 Hz, 1H), 6.66 (t, J=2.1 Hz, 1H), 3.72-3.68 (m, 4H), 3.57-3.53(m, 4H), 2.80 (t, J=5.2 Hz, 4H), 1.80 (p, 5.8 Hz, 4H), 1.59 (br s, 2H).

LCMS (m/z): 463.7 (MH⁺).

I-5:5-(6-aminopyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.64 (s, 1H), 8.50 (d, J=2.5Hz, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 7.41 (s, 1H), 7.28 (d, J=3.6 Hz,1H), 6.91 (d, J=3.6 Hz, 1H), 6.52 (d, J=8.7 Hz, 1H), 6.44 (s, 2H), 3.72(t, J=4.8 Hz, 4H), 3.50 (t, J=4.8 Hz, 4H), 2.83 (t, J=5.1 Hz, 4H), 1.77(br s, 4H), 1.58 (br s, 2H).

LCMS (m/z): 505.7 (MH⁺).

I-6:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.94 (s, 1H), 9.90 (s, 1H), 8.82 (d, J=1.9Hz, 1H), 8.67 (s, 1H), 8.46 (d, J=1.9 Hz, 1H), 7.57 (d, J=3.5 Hz, 1H),7.44 (s, 1H), 7.36 (d, J=3.6 Hz, 1H), 7.20 (d, J=3.7 Hz, 1H), 6.48 (d,J=3.4 Hz, 1H), 3.76-3.69 (m, 4H), 3.51 (t, J=4.8 Hz, 4H), 2.86 (t, J=5.0Hz, 4H), 1.83 (br s, 4H), 1.61 (br s, 2H).

LCMS (m/z): 529.9 (MH⁺).

I-7:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (s, 1H), 9.64 (s, 1H), 8.62 (s, 1H),8.18 (s, 1H), 7.91 (s, 1H), 7.39 (s, 1H), 7.28 (d, J=3.6 Hz, 1H), 6.77(d, J=3.6 Hz, 1H), 3.72 (t, J=4.8 Hz, 4H), 3.50 (t, J=4.8 Hz, 4H), 2.83(t, J=5.2 Hz, 4H), 1.77 (br s, 4H), 1.59 (br s, 2H).

LCMS (m/z): 479.7 (MH⁺).

I-8:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.21 (s, 1H), 9.76 (s, 1H), 8.64 (s, 1H),7.89 (s, 1H), 7.39 (s, 1H), 7.31 (d, J=3.6 Hz, 1H), 6.91 (d, J=3.6 Hz,1H), 6.66 (s, 1H), 3.72 (t, J=4.8 Hz, 4H), 3.50 (t, J=4.8 Hz, 4H), 2.83(t, J=5.1 Hz, 4H), 1.80 (br s, 4H), 1.59 (br s, 2H).

LCMS (m/z): 479.7 (MH⁺).

I-9:5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.85 (s, 1H), 8.63 (s, 1H), 8.54 (d, J=5.2Hz, 1H), 7.70 (s, 1H), 7.64 (d, J=5.2 Hz, 1H), 7.47 (d, J=3.7 Hz, 1H),7.43 (s, 1H), 7.40 (d, J=3.7 Hz, 1H), 3.75-3.69 (m, 4H), 3.54-3.48 (m,4H), 2.85 (t, J=5.1 Hz, 4H), 2.53 (s, 3H), 1.79 (br s, 4H), 1.61 (br s,2H).

LCMS (m/z): 504.7 (MH⁺).

I-10:5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.98 (s, 1H), 8.55 (d, J=5.2 Hz, 1H), 8.38(s, 1H), 7.69 (s, 1H), 7.63 (d, J=5.2 Hz, 1H), 7.47 (d, J=3.7 Hz, 1H),7.39 (d, J=3.7 Hz, 1H), 7.32 (s, 1H), 3.72-3.68 (m, 4H), 3.57-3.53 (m,4H), 2.83 (t, J=5.2 Hz, 4H), 2.53 (s, 3H), 1.80 (br s, 4H), 1.61 (br s,2H).

LCMS (m/z): 488.7 (MH⁺).

I-11:2-(6-aminopyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.76 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.49(s, 1H), 8.29 (s, 1H), 7.96 (dd, J=8.7, 2.5 Hz, 1H), 7.28 (s, 1H), 6.69(s, 2H), 6.54 (d, J=8.8 Hz, 1H), 3.73-3.68 (m, 4H), 3.58-3.53 (m, 4H),2.80 (t, J=5.1 Hz, 4H), 1.80 (br s, 4H), 1.59 (br s, 2H).

LCMS (m/z): 506.6 (MH⁺).

I-12:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 10.68 (s, 1H), 8.48 (s, 1H),8.41 (d, J=1.3 Hz, 1H), 8.30 (s, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.27 (s,1H), 3.74-3.67 (m, 4H), 3.59-3.53 (m, 4H), 2.81 (t, J=5.3 Hz, 4H), 1.81(br s, 4H), 1.61 (br s, 2H).

LCMS (m/z): 480.7 (MH⁺).

I-13:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 10.72 (s, 1H), 8.49 (s, 1H),8.37 (s, 1H), 7.99 (dd, J=2.4, 1.4 Hz, 1H), 7.27 (s, 1H), 6.76 (t, J=2.1Hz, 1H), 3.73-3.68 (m, 4H), 3.58-3.53 (m, 4H), 2.81 (t, J=5.2 Hz, 4H),1.83 (s, 4H), 1.61 (s, 2H).

LCMS (m/z): 480.7 (MH⁺).

I-14:2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.79 (s, 1H), 8.64 (d, J=5.0 Hz, 1H), 8.62(s, 1H), 8.49 (s, 1H), 7.91 (s, 1H), 7.77 (dd, J=5.2, 1.6 Hz, 1H), 7.31(s, 1H), 3.74-3.67 (m, 4H), 3.58-3.53 (m, 4H), 2.82 (t, J=5.1 Hz, 4H),2.57 (s, 3H), 1.83 (s, 4H), 1.63 (s, 2H).

LCMS (m/z): 505.7 (MH⁺).

I-15:5-(6-aminopyridin-3-yl)-N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.88 (s, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.37(s, 1H), 7.83 (dd, J=8.7, 2.4 Hz, 1H), 7.30-7.25 (m, 2H), 6.91 (d, J=3.6Hz, 1H), 6.52 (d, J=8.7 Hz, 1H), 6.44 (s, 2H), 3.60-3.54 (m, 4H), 2.80(t, J=5.1 Hz, 4H), 2.40 (t, J=5.1 Hz, 4H), 2.21 (s, 3H), 1.76 (s, 4H),1.58 (s, 2H).

LCMS (m/z): 502.8 (MH⁺).

I-16:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (s, 1H), 9.79 (s, 1H), 8.35 (s, 1H),8.18 (s, 1H), 7.90 (s, 1H), 7.29-7.25 (m, 2H), 6.77 (d, J=3.6 Hz, 1H),3.57 (t, J=4.9 Hz, 4H), 2.80 (t, J=5.1 Hz, 4H), 2.41 (s, 4H), 2.21 (s,3H), 1.77 (br s, 4H), 1.59 (br s, 2H).

LCMS (m/z): 476.8 (MH⁺).

I-17:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.21 (s, 1H), 9.92 (s, 1H), 8.36 (s, 1H),7.89 (s, 1H), 7.30 (d, J=3.4 Hz, 1H), 7.26 (s, 1H), 6.91 (d, J=3.6 Hz,1H), 6.66 (s, 1H), 3.57 (t, J=4.9 Hz, 4H), 2.80 (t, J=5.1 Hz, 4H), 2.40(t, J=5.0 Hz, 4H), 2.21 (s, 3H), 1.80 (br s, 4H), 1.60 (br s, 2H).

LCMS (m/z): 476.8 (MH⁺).

I-18:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.98 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 8.36(s, 1H), 7.69 (s, 1H), 7.63 (d, J=5.5 Hz, 1H), 7.48 (d, J=3.7 Hz, 1H),7.40 (d, J=3.7 Hz, 1H), 7.30 (s, 1H), 3.57 (t, J=5.0 Hz, 4H), 2.82 (t,J=5.0 Hz, 4H), 2.53 (s, 3H), 2.40 (t, J=5.1 Hz, 4H), 2.21 (s, 3H), 1.80(s, 4H), 1.61 (s, 2H).

LCMS (m/z): 501.7 (MH⁺).

I-19:2-(6-aminopyridin-3-yl)-N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.76 (s, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.47(s, 1H), 8.29 (s, 1H), 7.96 (dd, J=8.7, 2.5 Hz, 1H), 7.26 (s, 1H), 6.69(s, 2H), 6.54 (d, J=8.7 Hz, 1H), 3.57 (t, J=5.0 Hz, 4H), 2.80 (t, J=5.1Hz, 4H), 2.40 (t, J=5.0 Hz, 6H), 2.21 (s, 3H), 1.80 (br s, 4H), 1.59 (brs, 2H).

LCMS (m/z): 519.7 (MH⁺).

I-20:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 10.68 (s, 1H), 8.47 (s, 1H),8.41 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.25 (s, 1H), 3.57 (t, J=5.0Hz, 4H), 2.81 (t, J=4.9 Hz, 4H), 2.41 (t, J=5.0 Hz, 4H), 2.21 (s, 3H),1.82 (p, J=5.7 Hz, 5H), 1.60 (br s, 2H).

LCMS (m/z): 493.7 (MH⁺).

I-21:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 10.71 (s, 1H), 8.48 (s, 1H),8.37 (s, 1H), 7.99 (s, 1H), 7.25 (s, 1H), 6.76 (s, 1H), 3.62-3.52 (br m,4H), 2.86-2.77 (br m, 4H), 2.45-2.38 (br m, 4H), 2.21 (s, 3H), 1.83 (s,4H), 1.62 (br s, 2H).

LCMS (m/z): 493.8 (MH⁺).

I-22:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.80 (s, 1H), 8.68-8.61 (m, 2H), 8.49 (s,1H), 7.93 (s, 1H), 7.79 (d, J=6.1 Hz, 1H), 7.29 (s, 1H), 3.61-3.55 (brm, 4H), 2.86-2.80 (br m, 4H), 2.58 (s, 3H), 2.41 (br s, 4H), 2.21 (s,3H), 1.83 (br s, 4H), 1.65 (br s, 2H).

LCMS (m/z): 518.7 (MH⁺).

I-23:N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.25 (s, 1H), 9.65 (s, 1H), 8.34 (s, 1H),8.18 (s, 1H), 7.29 (d, J=3.7 Hz, 2H), 6.77 (d, J=3.7 Hz, 1H), 4.86 (brd, J=48.3 Hz, 1H), 3.73-3.67 (br m, 4H), 3.58-3.52 (br m, 4H), 3.04-2.93(br m, 2H), 2.88-2.75 (br m, 1H), 2.21-1.90 (br m, 1H).

LCMS (m/z): 481.8 (MH⁺).

I-24:N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.86 (s, 1H), 8.52 (d, J=5.1 Hz, 1H), 8.35(s, 1H), 7.68 (s, 1H), 7.62 (d, J=5.4 Hz, 1H), 7.47 (d, J=3.7 Hz, 1H),7.41 (d, J=3.7 Hz, 1H), 7.33 (s, 1H), 4.88 (br d, J=48.0 Hz, 1H), 3.71(t, J=4.8 Hz, 4H), 3.56 (t, J=4.8 Hz, 4H), 3.05-2.96 (br m, 2H),2.88-2.80 (br m, 2H), 2.52 (s, 3H), 2.21-1.95 (br m, 4H).

LCMS (m/z): 506.7 (MH⁺).

I-25:N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.43 (s, 1H), 10.56 (s, 1H), 8.48 (s, 1H),8.40 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 7.29 (s, 1H), 4.88 (br d,J=48.7 Hz, 1H), 3.70 (t, J=4.8 Hz, 4H), 3.56 (t, J=4.8 Hz, 4H),3.04-2.93 (br m, 2H), 2.90-2.78 (br m, 2H), 2.24-2.00 (br m, 4H).

LCMS (m/z): 498.7 (MH⁺).

I-26:N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.63 (s, 1H), 8.61 (d, J=5.8Hz, 1H), 8.49 (s, 1H), 7.85 (s, 1H), 7.75 (d, J=5.2 Hz, 1H), 7.32 (s,1H), 4.88 (br d, J=48.4 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.56 (t, J=4.8Hz, 4H), 3.07-2.94 (br m, 2H), 2.90-2.79 (br m, 2H), 2.56 (s, 3H),2.25-1.98 (br m, 4H).

LCMS (m/z): 523.8 (MH⁺).

I-27:N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.27 (s, 1H), 9.59 (s, 1H), 8.32 (s, 1H),8.17 (s, 1H), 7.89 (s, 1H), 7.34 (s, 1H), 7.30 (d, J=3.6 Hz, 1H), 6.77(d, J=3.6 Hz, 1H), 3.70 (t, J=4.8 Hz, 4H), 3.55 (t, J=4.8 Hz, 4H), 2.98(t, J=5.5 Hz, 4H), 2.31-2.14 (br m, 4H).

LCMS (m/z): 499.7 (MH⁺).

I-28:N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.80 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.31(s, 1H), 7.69 (s, 1H), 7.61 (d, J=5.2 Hz, 1H), 7.46 (d, J=3.7 Hz, 1H),7.42 (d, J=3.7 Hz, 1H), 7.37 (s, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.56 (t,J=4.8 Hz, 4H), 2.99 (t, J=5.5 Hz, 4H), 2.51 (s, 3H), 2.30-2.16 (br m,4H).

LCMS (m/z): 524.8 (MH⁺).

I-29:N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.46 (s, 1H), 10.50 (s, 1H), 8.47 (s, 1H),8.38 (s, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.35 (s, 1H), 3.71 (t, J=4.8Hz, 4H), 3.56 (t, J=4.8 Hz, 4H), 2.99 (t, J=5.6 Hz, 4H), 2.36-2.21 (brm, 4H).

LCMS (m/z): 516.6 (MH⁺).

I-30:N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.65 (s, 1H), 8.58 (d, J=5.1Hz, 1H), 8.49 (s, 1H), 7.83 (s, 1H), 7.74 (d, J=5.7 Hz, 1H), 7.39 (s,1H), 3.71 (t, J=4.8 Hz, 4H), 3.57 (t, J=4.8 Hz, 4H), 3.01 (t, J=5.6 Hz,4H), 2.56 (s, 3H), 2.34-2.20 (br m, 4H).

LCMS (m/z): 541.9 (MH⁺).

I-31:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (s, 1H), 9.78 (s, 1H), 8.33 (s, 1H),8.17 (s, 1H), 7.90 (s, 1H), 7.33-7.17 (m, 2H), 6.77 (d, J=3.7 Hz, 1H),3.56 (br s, 4H), 2.80 (t, J=5.1 Hz, 4H), 1.77 (br s, 4H), 1.60 (br s,8H).

LCMS (m/z): 461.7 (MH⁺).

I-32:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.21 (s, 1H), 9.91 (s, 1H), 8.35 (s, 1H),7.90 (s, 1H), 7.29 (d, J=3.7 Hz, 1H), 7.24 (s, 1H), 6.91 (d, J=3.7 Hz,1H), 6.66 (s, 1H), 3.56 (br s, 4H), 2.80 (br s, 4H), 1.80 (br s, 4H),1.59 (br s, 8H).

LCMS (m/z): 461.7 (MH⁺).

I-33:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.35(s, 1H), 7.69 (s, 1H), 7.63 (d, J=5.0 Hz, 1H), 7.47 (dd, J=3.6, 1.3 Hz,1H), 7.39 (dd, J=3.6, 1.3 Hz, 1H), 7.28 (d, J=1.3 Hz, 1H), 3.58-3.52 (m,4H), 2.84-2.80 (m, 4H), 2.53 (s, 3H), 1.84-1.78 (m, 4H), 1.63-1.54 (m,8H).

LCMS (m/z): 486.8 (MH⁺).

I-34:2-(6-aminopyridin-3-yl)-N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.75 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.46(s, 1H), 8.29 (s, 1H), 7.96 (dd, J=8.7, 2.4 Hz, 1H), 7.24 (s, 1H), 6.69(s, 2H), 6.54 (d, J=9.3 Hz, 1H), 3.57-3.53 (m, 4H), 2.84-2.76 (m, 4H),1.84-1.75 (m, 4H), 1.65-1.52 (m, 8H).

LCMS (m/z): 504.3 (MH⁺).

I-35:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 10.67 (s, 1H), 8.45 (s, 1H),8.41 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.22 (s, 1H), 3.60-3.52 (m,4H), 2.84-2.77 (m, 4H), 1.86-1.75 (m, 4H), 1.60 (br s, 8H).

LCMS (m/z): 478.7 (MH⁺).

I-36:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 10.71 (s, 1H), 8.46 (s, 1H),8.36 (s, 1H), 8.00 (s, 1H), 7.23 (s, 1H), 6.76 (s, 1H), 3.60-3.52 (m,4H), 2.85-2.77 (m, 4H), 1.86-1.79 (m, 4H), 1.60 (br s, 8H).

LCMS (m/z): 478.7 (MH⁺).

I-37:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.78 (s, 1H), 8.68-8.59 (m, 2H), 8.46 (s,1H), 7.92 (s, 1H), 7.78 (d, J=6.6 Hz, 1H), 7.26 (s, 1H), 3.59-3.52 (m,4H), 2.89-2.74 (m, 4H), 1.83 (q, J=6.8, 5.6 Hz, 4H), 1.60 (br s, 8H).

LCMS (m/z): 503.7 (MH⁺).

I-38:N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.22 (s, 1H), 9.77 (s, 1H), 8.43 (s, 1H),8.20 (s, 1H), 7.96 (s, 1H), 7.34 (s, 1H), 7.26 (d, J=3.6 Hz, 1H), 6.76(d, J=3.6 Hz, 1H), 4.96 (d, J=47.0 Hz, 1H), 3.74-3.68 (m, 4H), 3.57-3.53(m, 4H), 3.13-3.02 (m, 2H), 2.86-2.79 (m, 2H), 2.09-1.65 (m, 4H).

LCMS (m/z): 481.7 (MH⁺).

I-39:N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.94 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.43(s, 1H), 7.74 (s, 1H), 7.66 (d, J=5.2 Hz, 1H), 7.46 (d, J=3.7 Hz, 1H),7.40-7.36 (m, 2H), 4.97 (d, J=47.4 Hz, 1H), 3.74-3.68 (m, 4H), 3.59-3.53(m, 4H), 3.14-3.02 (m, 2H), 2.89-2.82 (m, 2H), 2.52 (s, 3H), 2.13-1.69(m, 4H).

LCMS (m/z): 506.9 (MH⁺).

I-40:N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.39 (s, 1H), 10.60 (s, 1H), 8.51 (s, 1H),8.43 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.32 (s, 1H), 4.97 (d, J=47.2Hz, 1H), 3.75-3.67 (m, 4H), 3.60-3.53 (m, 4H), 3.21 (dd, J=25.5, 11.5Hz, 1H), 3.09-2.98 (br m, 1H), 2.84-2.67 (br m, 2H), 2.11 (br s, 1H),2.01-1.81 (m, 2H), 1.71 (br s, 1H).

LCMS (m/z): 498.7 (MH⁺).

I-41:N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 8.62 (m, J=5.8 Hz, 2H), 8.53(s, 1H), 7.97 (s, 1H), 7.81 (d, J=5.8 Hz, 1H), 7.36 (s, 1H), 4.99 (d,J=50.0 Hz, 1H), 3.75-3.67 (m, 4H), 3.61-3.53 (m, 4H), 3.28-3.13 (br m,1H), 3.12-2.99 (br m, 1H), 2.86-2.69 (br m, 2H), 2.57 (s, 3H), 2.12 (brs, 1H), 2.02-1.79 (br m, 2H), 1.72 (br s, 1H).

LCMS (m/z): 523.9 (MH⁺).

I-42:N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.23 (s, 1H), 9.63 (s, 1H), 8.44 (s, 1H),8.15 (s, 1H), 7.93 (s, 1H), 7.40 (s, 1H), 7.26 (d, J=3.6 Hz, 1H), 6.77(d, J=3.6 Hz, 1H), 3.73-3.68 (m, 4H), 3.59-3.52 (m, 4H), 3.20 (br t,J=11.3 Hz, 2H), 2.89-2.82 (br m, 2H), 2.16-2.04 (br m, 2H), 1.95-1.87(br m, 2H).

LCMS (m/z): 499.7 (MH⁺).

I-43:N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 9.78 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.44(s, 1H), 7.68 (s, 1H), 7.63 (d, J=5.1 Hz, 1H), 7.47 (d, J=3.7 Hz, 1H),7.43 (s, 1H), 7.39 (d, J=3.7 Hz, 1H), 3.75-3.68 (m, 4H), 3.61-3.54 (m,4H), 3.25-3.15 (m, 2H), 2.92-2.86 (br m, 2H), 2.53 (s, 3H), 2.20-2.03(br m, 2H), 2.01-1.88 (m, 2H).

LCMS (m/z): 524.8 (MH⁺).

I-44:N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.39 (s, 1H), 10.53 (s, 1H), 8.52 (s, 1H),8.39 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.38 (s, 1H), 3.74-3.67 (m,4H), 3.60-3.54 (m, 4H), 3.25 (br d, J=12.0 Hz, 2H), 2.78 (br s, 2H),2.16-1.90 (br m, 4H).

LCMS (m/z): 516.6 (MH⁺).

I-45:N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.67-8.58 (m, 2H), 8.55 (s,1H), 7.93 (s, 1H), 7.79 (d, J=6.4 Hz, 1H), 7.42 (s, 1H), 3.74-3.67 (m,4H), 3.59-3.54 (m, 4H), 3.26 (d, J=11.1 Hz, 2H), 2.81 (s, OH), 2.58 (s,3H), 2.23-2.00 (m, OH), 1.95 (s, 2H).

LCMS (m/z): 541.7 (MH⁺).

I-46:N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.20 (s, 1H), 9.63 (s, 1H), 8.19 (s, 1H),7.95-7.85 (m, 2H), 7.26 (d, J=3.5 Hz, 1H), 7.13 (s, 1H), 6.72 (d, J=3.5Hz, 1H), 3.74-3.66 (m, 4H), 3.60-3.52 (m, 4H), 3.10-3.05 (br m, 4H),1.95-1.88 (br m, 4H).

LCMS (m/z): 449.7 (MH⁺).

I-47:N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 10.40 (s, 1H), 8.40 (s, 2H),8.29 (s, 1H), 7.98 (s, 1H), 7.29 (s, 1H), 3.74-3.67 (m, 4H), 3.60-3.52(m, 4H), 3.06-2.99 (br m, 4H), 2.00-1.96 (br m, 4H).

LCMS (m/z): 466.6 (MH⁺).

I-48:N-(2,5-dimorpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.28 (s, 1H), 9.75 (s, 1H), 8.37 (s, 1H),8.22 (s, 1H), 7.94 (s, 1H), 7.36 (s, 1H), 7.29 (d, J=3.6 Hz, 1H), 6.77(d, J=3.6 Hz, 1H), 3.87-3.79 (m, 4H), 3.74-3.67 (m, 4H), 3.59-3.53 (m,4H), 2.90-2.82 (m, 4H).

LCMS (m/z): 465.7 (MH⁺).

I-49:N-(2,5-dimorpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.45 (s, 1H), 10.64 (s, 1H), 8.50 (s, 1H),8.45 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.35 (s, 1H), 3.91-3.85 (m,4H), 3.74-3.67 (m, 4H), 3.60-3.52 (m, 4H), 2.90-2.83 (m, 4H).

LCMS (m/z): 482.7 (MH⁺).

I-50:N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (s, 1H), 9.78 (s, 1H), 8.33 (s, 1H),8.17 (s, 1H), 7.90 (s, 1H), 7.27 (d, J=3.6 Hz, 1H), 7.23 (s, 1H), 6.77(d, J=3.6 Hz, 1H), 3.65 (t, J=5.2 Hz, 2H), 3.56 (t, J=5.2 Hz, 2H), 3.25(s, 3H), 3.13 (s, 3H), 2.84-2.76 (m, 4H), 1.82-1.73 (br m, 4H),1.65-1.54 (br m, 2H).

LCMS (m/z): 465.7 (MH⁺).

I-51:N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 10.67 (s, 1H), 8.45 (s, 1H),8.41 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.22 (s, 1H), 3.65 (t, J=5.6Hz, 2H), 3.57 (t, J=5.6 Hz, 2H), 3.25 (s, 3H), 3.13 (s, 3H), 2.85-2.77(m, 4H), 1.87-1.76 (m, 4H), 1.66-1.55 (m, 2H).

LCMS (m/z): 482.6 (MH⁺).

I-52:N-(2-((2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 10.67 (s, 1H), 8.40 (s, 2H),8.27 (s, 1H), 8.01 (s, 1H), 7.79 (t, J=5.8 Hz, 1H), 7.20 (s, 1H),3.58-3.51 (m, 4H), 3.39 (q, J=6.4 Hz, 2H), 2.84-2.77 (m, 4H), 2.53-2.49(m, 2H), 2.44-2.37 (m, 4H), 1.86-1.76 (m, 4H), 1.65-1.55 (m, 2H).

LCMS (m/z): 523.7 (MH⁺).

I-53:N-(2-(methyl(2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (s, 1H), 9.78 (s, 1H), 8.32 (s, 1H),8.17 (s, 1H), 7.90 (s, 1H), 7.26 (d, J=3.6 Hz, 1H), 7.23 (s, 1H), 6.77(d, J=3.6 Hz, 1H), 3.59 (t, J=6.4 Hz, 2H), 3.53-3.45 (m, 4H), 3.12 (s,3H), 2.84-2.76 (m, 4H), 2.54 (t, J=6.4 Hz, 2H), 2.45-2.38 (m, 4H),1.82-1.71 (m, 4H), 1.63-1.54 (m, 2H).

LCMS (m/z): 520.7 (MH⁺).

I-54:N-(2-(methyl(2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 10.66 (s, 1H), 8.44 (s, 1H),8.41 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.21 (s, 1H), 3.59 (t, J=6.4Hz, 2H), 3.54-3.45 (m, 4H), 3.12 (s, 3H), 2.85-2.76 (m, 4H), 2.54 (t,J=6.4 Hz, 2H), 2.45-2.39 (m, 4H), 1.86-1.77 (m, 4H), 1.66-1.55 (m, 2H).

LCMS (m/z): 537.8 (MH⁺).

Example 9 LPS induced IL23p19 in THP-1 cells (with IFNγ primed) AssayMaterials and Equipment

THP-1 Cells (ATCC, Cat# TIB-202), Dimethyl Sulfoxide (DMSO)(Sigma-Aldrich, Cat# D2650), RPMI 1640 (Cellgro, Cat#10-040-CM), FetalBovine Serum (Sigma, Cat# F4135), Albumin From Bovine Serum (BSA)(Sigma-Aldrich, Cat#A7906), LPS (Serotype K-235, Sigma, Product Number L2143), IFNγ (Peprotech, Cat#300-02)

Capture antibody: Human IL-23p19 ELISA (e-Bioscience, Cat. #14-7238-85),Detection antibody: Primary Mouse Biotinylated anti-human IL-12(p40/p70) (e-Bioscience, Cat. #13-7129-85), Secondary HRP-conjugatedStreptavidin (R&D Systems, Cat#DY998), 1×PBST Washing Buffer (PBS-Tweentablet) (VWR International, Cat#80058-558), ELISA Blocking Buffer (PBSwith 1% BSA), ELISA Dilution Buffer (PBS with 1% BSA), 384 WellFlat-Bottom, MaxiSorp Black Immuno Plates (Thermo Scientific,Cat#12-565-346), 384 Well Flat-Bottom, White Tissue Culture Plates(Thermo Scientific, Cat#12-565-343), Super Signal ELISA PicoChemiluminescent Substrate (Thermo Scientific, Cat#37070), Cell TiterGlo reagent (Promega, Cat#G7573), Positive control, IKK2VI inhibitor(Calbiochem, Cat#401483), AquaMax 4000 plate washer (Molecular Devices),Luminometer, Wallac Victor2 1420 Multilabel Counter.

Method THP-1 Cells Stimulation:

On day 1, 50K/well THP-1 cells were seeded and primed with IFNγ (50ng/mL) in 384-well plates for about 18 hours in RPMI media with 10% FBS.On day 2, the compound was serially diluted in DMSO from 5 mM in 3-folddilutions, and then diluted 1:125 in RPMI media with 10% FBS. 50 μL/well2× compound was added to 50 μL/well THP-1 cells (with IFNγ primed) induplicate in 384 well tissue culture plates. The cells werepre-incubated with compound for 1 hour at 37° C., 5% CO₂ before additionof 10 μL/well 11×LPS to give a final concentration of 1 ug/mL LPS. Day3, after stimulation for 18 hours at 37° C., 5% CO₂, the assay plate wascentrifuged and 70 μL/well supernatant was harvested. IL-23p19 proteinin 70 μL/well of supernatant was measured by sandwich ELISA, and 25al/well Cell Titer Glo reagent was added to the remaining cells tomeasure compound toxicity.

Human IL-23p19 Sandwich ELISA:

Maxisorp immuno ELISA plates were pre-coated with 25 μL/well ofanti-IL-23p19 capture antibody (2.5 ug/mL) in PBS overnight at roomtemperature. After washing with 1×PBST, the plates were blocked using100 μL/well of 1% BSA in PBS for 2 hours at room temperature. The plateswere washed three times with 1×PBST and 70 μL/well supernatant wereadded. The plates were incubated at room temperature for 2 hours withshaking and washed three times with 1×PBST. 25 μL/well of biotin labeledanti-IL-12 (p40/p70) detection antibody (100 ng/mL) in PBS with 1% BSAwas added and the plates were incubated at room temperature for 2 hourswith shaking. After washing three times with 1×PBST, 25 μL/well ofstreptavidin-HRP (1:200) in PBS with 1% BSA was added and the plateswere incubated at room temperature for 20 minutes with shaking. Theplates were washed three times with 1×PBST and 25 μL/well of SuperSignal ELISA Pico Chemiluminescent Substrate were added. The plates wereread with a luminometer, and the chemiluminescence values were enteredinto Athena (Rigel) for curve fitting, EC₅₀ calculation, and databasestorage. The results are shown in Table 1.

Example 10 Compound Screening Using DC Cells Materials

Human PBMC cells (All Cells, Cat No. PB002)RPMI growth media containing 10% FBS

IFNγ (Peprotech, Cat No. 300-02) GMCSF (Peprotech, Cat No. 300-03) andIL4 (Peprotech Cat No. 200-04)

White clear bottom 96 well plates (Fisher, Cat No. 07-200-587, Corning#3903)LPS (Make 2.5 mg/ml Stock in PBS) from Sigma Aldrich (Cat No. L2018-5MG)Cell Titer Glo reagent (Promega, Cat No. G7573)Positive controls, IKK2VI inhibitor (Calbiochem, Cat No. 401483)

Protocol

I. Differentiation of PBMC's to DC cells:

Human PBMC cells (400 million) obtained from the vendor were transferredinto a T-175 flask containing 15 ml RPMI media (10% FBS) and incubatefor 2 hours at 37° C. After 2 hours, the media including floating cellswas aspirated out carefully and 12 ml of fresh RPMI media (10% FBS)containing GMCSF (100 ng/ml) and IL4 (20 ng/ml) was added, and the flaskwas kept in a 37° C. incubator for 7 days.

After 3 days, fresh GMCSF (100 ng/ml) and IL4 (20 ng/ml) were added tothe flask and the incubation continued. After 7 days, the fullydifferentiated cells were harvested by spinning down (1200 rpm/5 min)and aspirating the media. The cells were suspended in fresh RPMI media(10% FBS) containing 50 ng/ml IFNγ (1000 U/ml) and then plated (50K/wellin 100 μl) onto a white clear bottom 96 well plate and left in a 37° C.incubator for 24 hours.

II. Addition of Compounds:

After 24 hours incubation, 100 μl of RPMI media was added containing 2×concentrated test compound per well to the above cell-culture media(final concentration becomes IX) and the plates were pre-incubated for 1hour at 37° C. before stimulating with LPS.

After 1 hour compound pre-incubation, 10 μl per well of 20× concentratedLPS solution in RPMI media was added to give a final concentration of 1μg/ml. The mixture was shaken and incubated the plates at 37° C. for anadditional 18 hours.

155 μl of the supernatant was harvested from each well carefully(without the tip touching the bottom of the well) and to the remaining50 μl/well of the cell culture plate was added 50 al of Cell Titer Gloreagent. The mixture was incubated for 1-2 minutes on a shaker and theplate was read for luminescence intensity to determine the compoundcytotoxicity. The cell culture supernatant collected above was used tocarry out IL23 ELISA (65 μl-Supernatant) and IL10 ELISA (90μl-Supernatant) as described below.

Example 11 Human IL-23 (pl9/p40) ELISA Protocol (e-BiosciencesMaterials:

96-well high binding opaque white plates (from Pierce, Cat No. 15042);

1×PBS; 1×TBST washing buffer;Blocking Solution: 0.5% Casein in PBS (from BDH, Cat No. 440203H);Dilution Solution: 1% BSA in PBS (10% BSA from Fisher, Cat No. 37525);Capture antibody: Rat anti-human IL-23 (p19) (e-Biosciences, Cat. No.14-7238-85);Detection antibody: Primary Mouse Biotinylated anti-human IL-12(p40/p70) (e-biosciences, Cat No. 13-7129-85);Secondary HRP-conjugated Streptavidin (R&D Systems, Cat No. DY998);rHuman-IL-23 (e-biosciences, Cat No. 34-8239) (Suggested startingconcentration=5 ng/ml in RPMI cell culture media);Cell Culture Supernatant (65 μl from THP-1 cells primed with IFNγ (50ng/ml-1000 U/ml) and stimulated with 0.01% SAC);SuperSignal ELISA Pico Chemiluminescent substrate [Pierce, Cat No.37069].

Coating Plates:

To 10.5 ml PBS add 50 μl of anti-IL23 (p19) was added capture antibody(2.5 μg/ml). The mixture was mixed well and 100 al of the coatingsolution was added to each well of the 96 well white plates from Pierce.The wells were covered and incubated overnight at 4° C.

Blocking the Plates:

The anti-IL23 (p19)-antibody-coated plates were washed 2× using TBST(use plate washer) and blocked using 200 μl of 0.5% Casein for 1.5-2hours at room temperature with shaking.

Addition of Supernatant and Detection:

The plates were washed 2× using TBST and the supernatant was transferred(65 μl/well) to the above pre-blocked/IL23 (p19)-antibody-coated 96 wellplate, and incubated at room temperature for 1.5 hours with shaking.

The plates were washed 4× using TBST (plate washer) and 100 μl/welldetection antibody solution prepared from 2 μl of biotin labeledanti-IL-12 (p40/p70) antibody in 11 ml 1% BSA/PBS solution (1-5000dilution) was added. The plates were incubated for 1 hour with shakingat Room temperature.

Again, the plates were washed 4× with TBST and 100 μl of HRP labeledStreptavidin (R&D Systems) solution (10 μl/10 ml 1% BSA solution) wasadded, and the plates were incubated at room temperature for another 45minutes with shaking.

After 45 minutes, the plates were washed with TBST 4× and 100 ul/wellSuper Signal ELISA Pico Chemiluminescent Substrate from Pierce (3.5 mlA+3.5 ml B+3.5 ml MQ water) was added. The plates were shaken for 1-2minutes then read on a plate reader. The results are shown in Table 1.

TABLE 1 EC₅₀ results from the assays described in Examples 9 and 11IL23-p19 IL23-p19 ELISA, ELISA, Dendritic, THPI-IFNy, LPS, 10 pt LPS, 10pt Compound EC₅₀ (μM) EC₅₀ (μM) I-1 4.728 0.8979 I-2 9999 9999 I-30.0391 0.0314 I-4 12.13 0.9006 I-5 0.2571 0.4316 I-6 13.99 40.53 I-70.0136 0.026 I-8 9999 0.6142 I-9 0.8967 52.09 I-10 2.987 4.631 I-11 9999228.5 I-12 0.02 0.0539 I-13 9999 2.934 I-14 17.91 10.22 I-15 1.688 73.05I-16 0.0322 0.0258 I-17 1.021 1.228 I-18 0.889 7.511 I-19 0.6743 0.9384I-20 0.018 0.0224 I-21 1.706 2.176 I-22 3.183 0.6772 I-23 0.1568 0.0757I-24 5.774 1.08 I-25 0.1215 0.0482 I-26 9999 1.183 I-27 0.7471 0.5275I-28 9999 9999 I-29 0.1057 0.3022 I-30 9999 43.48 I-31 0.4438 0.1441I-32 24.1 1.781 I-33 9999 4454 I-34 9999 8.325 I-35 0.6658 0.3212 I-369999 5.237 I-37 9999 23.09 I-38 0.0141 0.0316 I-39 8.074 0.3549 I-400.041 0.025 I-41 2.584 0.1474 I-42 0.0848 0.0606 I-43 2.624 0.3436 I-440.1008 0.0887 I-45 0.4023 0.3422 I-46 0.0375 0.0587 I-47 0.058 0.0213I-48 0.1231 0.0585 I-49 0.0481 0.0504 I-50 0.0757 0.1326 I-51 0.04110.0742 I-52 0.0371 0.02 I-53 0.1213 0.1797 I-54 0.0603 0.1057 I-550.0303 0.024

In view of the many possible embodiments to which the principles of thedisclosed invention may be applied, it should be recognized that theillustrated embodiments are only preferred examples of the invention andshould not be taken as limiting the scope of the invention. Rather, thescope of the invention is defined by the following claims. We thereforeclaim as our invention all that comes within the scope and spirit ofthese claims.

We claim:
 1. A compound having a formula

or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, orprodrug thereof, wherein: X is O or S; Y is O or S; Z is N or CR⁹; Het-1is heterocyclyl; R¹ and R² independently are H, aliphatic,heteroaliphatic, heterocyclyl, aryl, araliphatic, or together with thenitrogen to which they are attached, form a heterocyclic ring; R³, R⁴,R⁵, R⁶ and R⁹ independently are H, aliphatic, halo, heteroaliphatic,—O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl,hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino,sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl; R⁷ is H,aliphatic, heteroaliphatic, heterocyclyl, aryl or araliphatic; each R⁸independently is aliphatic, halo, heteroaliphatic, —O-aliphatic,heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro,cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl,sulfonamide, sulfanyl, sulfinyl or haloalkyl; and m is from 0 to thenumber of possible substituents on Het-1.
 2. The compound of claim 1,wherein Het-1 is heteroaryl.
 3. The compound of claim 1, wherein Het-1is selected from furan, thiophene, pyrazole, pyrrole, imidazole,oxazole, thiazole, isoxazole, isothiazole, 1,2,3-triazole,1,2,4-triazole, 1,3,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,5-oxadiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrazole,pyrimidine, pyridine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine,pyrazine, pyridazine, quinoline, isoquinoline, indole, isoindole,benzofuran, benzothiophene, benzoimidazole, benzopyrazole,benzotriazole, pyrrolo[2,3-b]pyridine, pyrrolo[3,2-b]pyridine,pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,4-b]pyridineor pyrrolo[3,4-c]pyridine.
 4. The compound of claim 3, wherein Het-1 ispyridine, pyrazole or pyrrolo[2,3-b]pyridine.
 5. The compound of claim4, wherein Het-1 is selected from

and R¹⁰ and R²³ are selected from H, aliphatic, heteroaliphatic,—O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl,hydroxyl, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl,sulfonamide, or haloalkyl.
 6. The compound of claim 1, wherein

is selected from


7. The compound of claim 5, wherein: each R⁸ independently is selectedfrom halo, C₁₋₆ haloalkyl, C₁₋₆ alkyl, —OC₁₋₆ alkyl, amino or—CH₂OP(O)(OR²⁴)₂; and each R²⁴ independently is H, C₁₋₆ alkyl or acounterion forming a pharmaceutically acceptable base addition salt withthe phosphate moiety.
 8. The compound of claim 7, wherein at least oneR⁸ is —NH₂, —CH₃, —CF₃, —CF₂H or —CH₂CF₃.
 9. The compound of claim 1,wherein X is O.
 10. The compound of claim 1, wherein X is S.
 11. Thecompound of claim 1, wherein the compound has a formula selected from


12. The compound of claim 1, wherein the compound has formula selectedfrom

and R¹⁰ and R²³ are selected from H, aliphatic, heteroaliphatic,—O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl,hydroxyl, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl,sulfonamide, or haloalkyl.
 13. The compound of claim 1, wherein thecompound has a formula selected from

R¹⁰ and R²³ independently are H, aliphatic, aryl or heterocyclyl; andR¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²²independently are H, aliphatic, halogen, heteroaliphatic, —O-aliphatic,heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro,cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl,sulfonamide, sulfanyl, sulfinyl, or haloalkyl.
 14. The compound of claim13, wherein the compound has a formula selected from


15. The compound of claim 13, wherein the compound has a formulaselected from


16. The compound of claim 1, wherein R⁵ is amino, aryl or heteroaryl.17. The compound of claim 16, wherein R⁵ is amino having a formula —NRRwherein each R independently is aliphatic, or both R groups togetherwith the nitrogen attached thereto form a heterocyclic ring.
 18. Thecompound of claim 17, wherein R⁵ is a cyclic amino selected from


19. The compound of claim 16, wherein R⁵ is


20. The compound of claim 1, wherein R¹ and R² independently are H,aliphatic, heteroaliphatic, or together with the nitrogen attachedthereto forms a heteroaliphatic ring.
 21. The compound of claim 20,wherein R¹ is H or alkyl, and R² is aliphatic or heteroaliphatic. 22.The compound of claim 1, wherein R¹ and R², together with the nitrogenattached thereto, are selected from

R^(a) is aliphatic, haloalkyl or acyl; n is 1 or 2; and p is 0, 1 or 2.23. The compound of claim 22, wherein: R^(a) is CH₃, CF₃, CF₂H, orR^(b)C(O)—; and R^(b) is aliphatic or haloalkyl.
 24. A compound selectedfrom I-1:5-(6-aminopyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)furan-2-carboxamide;I-2:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)furan-2-carboxamide;I-3:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-4:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;I-5:5-(6-aminopyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)furan-2-carboxamide;I-6:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)furan-2-carboxamide;I-7:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-8:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;I-9:5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)furan-2-carboxamide;I-10:5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)furan-2-carboxamide;I-11:2-(6-aminopyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide;I-12:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-13:N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;I-14:2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide;I-15:5-(6-aminopyridin-3-yl)-N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)furan-2-carboxamide;I-16:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-17:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;I-18:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;I-19:2-(6-aminopyridin-3-yl)-N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide;I-20:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-21:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;I-22:N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;I-23:N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-24:N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;I-25:N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-26:N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;I-27:N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-28:N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;I-29:N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-30:N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;I-31:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-32:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;I-33:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;I-34:2-(6-aminopyridin-3-yl)-N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)thiazole-4-carboxamide;I-35:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-36:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;I-37:N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;I-38:N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-39:N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;I-40:N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-41:N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;I-42:N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-43:N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;I-44:N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-45:N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide;I-46:N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-47:N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-48:N-(2,5-dimorpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-49:N-(2,5-dimorpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-50:N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-51:N-(2-((2-methoxyethyl)(methyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-52:N-(2-((2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-53:N-(2-(methyl(2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;I-54:N-(2-(methyl(2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;I-55:N-(2-((2-morpholinoethyl)amino)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide,prodrug or combination thereof.
 25. A composition, comprising a compoundof claim 1, and a pharmaceutically acceptable excipient.
 26. A method,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 27. The method of claim 26,wherein the method is a method for treating a disease or condition forwhich an IRAK modulator or inhibitor is indicated.
 28. The method ofclaim 27, wherein the disease is an auto-immune disease, inflammatorydisorder, cardiovascular disease, nerve disorder, neurodegenerativedisorder, allergic disorder, multi-organ failure, kidney disease,platelet aggregation, cancer, transplantation, sperm motility,erythrocyte deficiency, graft rejection, lung injury, respiratorydisease, ischemic condition, bacterial infection, viral infection,immune regulatory disorder or a combination thereof.
 29. The method ofclaim 26, further comprising administering an additional therapeuticagent.
 30. The method of claim 29, wherein the additional therapeuticagent is an immunooncology agent.
 31. A method for inhibiting ormodulating an IRAK protein, comprising contacting the IRAK protein withan effective amount of a compound of claim 1.